Heterocyclic compounds as immunomodulators

ABSTRACT

Disclosed are compounds of Formula (I′), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.

CLAIM OF PRIORITY

This application is a continuation of U.S. patent application Ser. No.17/018,653, filed on Sep. 11, 2020, which is a continuation of U.S.patent application Ser. No. 16/750,941, filed on Jan. 23, 2020; which isa continuation of U.S. patent application Ser. No. 16/434,492, filed onJun. 7, 2019; which is a continuation of U.S. patent application Ser.No. 16/164,032, filed on Oct. 18, 2018; which is a continuation of U.S.patent application Ser. No. 15/902,549, filed on Feb. 22, 2018; which isa continuation of U.S. patent application Ser. No. 15/386,052, filed onDec. 21, 2016; which claims the benefit of U.S. Provisional ApplicationNo. 62/385,341, filed on Sep. 9, 2016; U.S. Provisional Application No.62/324,502, filed on Apr. 19, 2016; and U.S. Provisional Application No.62/270,931, filed on Dec. 22, 2015, each of which is incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The present application is concerned with pharmaceutically activecompounds. The disclosure provides compounds as well as theircompositions and methods of use. The compounds modulate PD-1/PD-L1protein/protein interaction and are useful in the treatment of variousdiseases including infectious diseases and cancer.

BACKGROUND OF THE INVENTION

The immune system plays an important role in controlling and eradicatingdiseases such as cancer. However, cancer cells often develop strategiesto evade or to suppress the immune system in order to favor theirgrowth. One such mechanism is altering the expression of co-stimulatoryand co-inhibitory molecules expressed on immune cells (Postow et al, J.Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitoryimmune checkpoint, such as PD-1, has proven to be a promising andeffective treatment modality.

Programmed cell death-1 (PD-1), also known as CD279, is a cell surfacereceptor expressed on activated T cells, natural killer T cells, Bcells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005,23:515-548; Okazaki and Honjo, Trends Immunol 2006, (4):195-201). Itfunctions as an intrinsic negative feedback system to prevent theactivation of T-cells, which in turn reduces autoimmunity and promotesself-tolerance. In addition, PD-1 is also known to play a critical rolein the suppression of antigen-specific T cell response in diseases likecancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239-245;Postow et al, J. Clinical Oncol 2015, 1-9).

The structure of PD-1 consists of an extracellular immunoglobulinvariable-like domain followed by a transmembrane region and anintracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553). Theintracellular domain contains two phosphorylation sites located in animmunoreceptor tyrosine-based inhibitory motif and an immunoreceptortyrosine-based switch motif, which suggests that PD-1 negativelyregulates T cell receptor-mediated signals. PD-1 has two ligands, PD-L1and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al,Nat Immunol 2001, 2, 261-268), and they differ in their expressionpatterns. PD-L1 protein is upregulated on macrophages and dendriticcells in response to lipopolysaccharide and GM-CSF treatment, and on Tcells and B cells upon T cell receptor and B cell receptor signaling.PD-L1 is also highly expressed on almost all tumor cells, and theexpression is further increased after IFN-γ treatment (Iwai et al, PNAS2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5). Infact, tumor PD-L1 expression status has been shown to be prognostic inmultiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al,Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). PD-L2expression, in contrast, is more restricted and is expressed mainly bydendritic cells (Nakae et al, J Immunol 2006, 177:566-73). Ligation ofPD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal thatinhibits IL-2 and IFN-γ production, as well as cell proliferationinduced upon T cell receptor activation (Carter et al, Eur J Immunol2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34). Themechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibitT cell receptor signaling such as Syk and Lck phosphorylation (Sharpe etal, Nat Immunol 2007, 8, 239-245). Activation of the PD-1 signaling axisalso attenuates PKC-θ activation loop phosphorylation, which isnecessary for the activation of NF-κB and AP1 pathways, and for cytokineproduction such as IL-2, IFN-γ and TNF (Sharpe et al, Nat Immunol 2007,8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman etal, J Exp Med 2000, 192(7):1027-34).

Several lines of evidence from preclinical animal studies indicate thatPD-1 and its ligands negatively regulate immune responses.PD-1-deficient mice have been shown to develop lupus-likeglomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322). Using anLCMV model of chronic infection, it has been shown that PD-1/PD-L1interaction inhibits activation, expansion and acquisition of effectorfunctions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439,682-7). Together, these data support the development of a therapeuticapproach to block the PD-1-mediated inhibitory signaling cascade inorder to augment or “rescue” T cell response. Accordingly, there is aneed for new compounds that block PD-1/PD-L1 protein/proteininteraction.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I′):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinconstituent variables are defined herein.

The present disclosure further provides a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinconstituent variables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, and at least onepharmaceutically acceptable carrier or excipient.

The present disclosure further provides methods of modulating orinhibiting PD-1/PD-L1 protein/protein interaction, which comprisesadministering to an individual a compound of the disclosure, or apharmaceutically acceptable salt or a stereoisomer thereof.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt or a stereoisomer thereof.

DETAILED DESCRIPTION I. Compounds

The present disclosure provides, inter alia, compounds of Formula (I′):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

-   -   X¹ is N or CR¹;    -   X² is N or CR²;    -   X³ is N or CR³;    -   X⁴ is N or CR⁴;    -   X⁵ is N or CR⁵;    -   X⁶ is N or CR⁶    -   wherein X¹, X² and X³ are not all simultaneously N;    -   wherein X⁴, X⁵ and X⁶ are not all simultaneously N;    -   X⁷ is N or CR^(8a);    -   X is N or CR^(8b);    -   X⁹ is N or CR^(8c);    -   Cy is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- to 14-membered        heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which        is optionally substituted with 1 to 4 independently selected R⁹        substituents;    -   R¹, R², R³, R⁴, R⁵, R⁶ and R⁹ are each independently selected        from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a),        C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),        NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),        NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),        NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),        NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a),        and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹, R², R³,        R⁴, R⁵, R⁶ and R⁹ are each optionally substituted with 1, 2, 3,        or 4 R^(b) substituents;    -   R⁷ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, OR¹¹, SR¹¹, NH₂, NHR¹¹, NR¹¹R¹¹, NHOR¹¹, C(O)R¹¹,        C(O)NR¹¹R¹¹, C(O)OR¹¹, OC(O)R¹¹, OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹,        NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹, C(═NR¹¹)NR¹¹R¹¹,        NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹,        NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and        S(O)₂NR¹¹R¹¹, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-14 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- of R⁹ and R¹¹ are each        optionally substituted with 1, 2 or 3 R^(b) substituents;    -   each R¹¹ is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R¹¹ are each optionally        substituted with 1, 2 or 3 independently selected R^(b)        substituents;    -   R^(8a), R^(8b) and R^(8c) are each independently selected from        H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄alkyl-,        C₆₋₁₀ aryl, C₆₋₁₀aryl-C₁₋₄alkyl-, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄        alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₂₋₄        alkenyl, C₂₋₄ alkynyl, halo, CN, OR¹⁰, C₁₋₄ haloalkyl, C₁₋₄        haloalkoxy, NH₂, —NHR¹⁰, —NR¹⁰R¹⁰, NHOR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹⁰,        C(O)OR¹⁰, OC(O)R¹⁰, OC(O)NR¹⁰R¹⁰, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)OR¹⁰,        NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰, C(═NR¹⁰)NR¹⁰R¹⁰,        NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰,        NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and        S(O)₂NR¹⁰R¹⁰, wherein each R¹⁰ is independently selected from H,        C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₃₋₆        cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄alkyl-, C₆₋₁₀aryl,        C₆₋₁₀aryl-C₁₋₄alkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and        (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₄        alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl,        C₃₋₆ cycloalkyl-C₁₋₄alkyl-, C₆₋₁₀aryl, C₆₋₁₀aryl-C₁₋₄alkyl-,        5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10        membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(8a), R^(8b), R^(8c) and R¹⁰        are each optionally substituted with 1, 2 or 3 independently        selected R^(d) substituents;    -   or two adjacent R⁹ substituents together with the atoms to which        they are attached, form a fused phenyl ring, a fused 5- to        7-membered heterocycloalkyl ring, a fused 5- or 6-membered        heteroaryl ring or a fused C₃₋₁₀ cycloalkyl ring, wherein the        fused 5- to 7-membered heterocycloalkyl ring and fused 5- or        6-membered heteroaryl ring each have 1-4 heteroatoms as ring        members selected from N, O and S and wherein the fused phenyl        ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or        6-membered heteroaryl ring and fused C₃₋₁₀ cycloalkyl ring are        each optionally substituted with 1, 2 or 3 independently        selected R^(b) substituents;    -   each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,        C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(d) substituents;    -   each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄        alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),        C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),        NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),        NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),        NR^(e)C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NOH)NR^(e)R^(e),        NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e),        S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and        S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl,        C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are        each optionally substituted with 1-3 independently selected        R^(h) substituents;    -   each R^(b) substituent is independently selected from halo, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c),        OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),        OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),        NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c),        NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),        NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c),        S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c);        wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀        aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each further        optionally substituted with 1-3 independently selected R^(d)        substituents;    -   each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(f) substituents        independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g),        C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),        NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),        NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),        NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g),        S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and        S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(a) substituents        independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo,        CN, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),        C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),        NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),        C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),        S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),        NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o);    -   each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionally        substituted with 1-3 R^(p) substituents independently selected        from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,        (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN,        NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r),        C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r),        NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),        C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),        NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),        S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r),        NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), wherein the C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,        C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionally        substituted with 1, 2 or 3 R^(q) substituents;    -   or any two R^(a) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or        10-membered heterocycloalkyl group optionally substituted with        1, 2 or 3 R^(h) substituents independently selected from C₁₋₆        alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-,        (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i),        C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i),        OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),        NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),        NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i),        S(O)₂R^(i), NR'S(O)₂R^(i), NR'S(O)₂NR^(i)R^(i), and        S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-,        and (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are        each further optionally substituted by 1, 2, or 3 R^(j)        substituents independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀        aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,        CN, NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k),        C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k),        NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k),        C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k),        S(O)NR^(k)R^(k), S(O)₂R^(k), NRS(O)₂R^(k),        NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), wherein the C₁₋₄        alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl,        4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        C₁₋₄haloalkyl, and C₁₋₄haloalkoxy of R^(j) are each optionally        substituted with 1, 2 or 3 independently selected R^(q)        substituents; or two R^(h) groups attached to the same carbon        atom of the 4- to 10-membered heterocycloalkyl taken together        with the carbon atom to which they are attached form a C₃₋₆        cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2        heteroatoms as ring members selected from O, N or S;    -   or any two R^(c) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(e) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(g) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(i) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(k) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(o) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents; and    -   each R^(e), R^(i), R^(k), R^(o) or R^(r) is independently        selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or        6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₁₋₄        haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄        alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,        4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of        R^(e), R^(i), R^(k), R^(o) or R^(p) are each optionally        substituted with 1, 2 or 3 R^(q) substituents;    -   each R^(q) is independently selected from OH, CN, —COOH, NH₂,        halo, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,        phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,        C₃₋₆ cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄ haloalkoxy, wherein        the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered        heterocycloalkyl, and 5-6 membered heteroaryl of R^(q) are each        optionally substituted with halo, OH, CN, —COOH, NH₂, C₁₋₄alkyl,        C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀        cycloalkyl, 5-6 membered heteroaryl and 4-6 membered        heterocycloalkyl and each R¹² is independently C₁₋₆ alkyl;    -   provided that R⁷ is other than NH₂, when X⁸ is CR^(8b) and X⁷        and X⁹ are each N; and the compound is other than        (1R,5S,6R)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine        or        (1S,5R,6S)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine.

The present disclosure provides compounds of Formula (I′), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

-   -   X¹ is N or CR¹;    -   X² is N or CR²;    -   X³ is N or CR³;    -   X⁴ is N or CR⁴;    -   X⁵ is N or CR⁵;    -   X⁶ is N or CR⁶    -   wherein X¹, X² and X³ are not all simultaneously N;    -   wherein X⁴, X⁵ and X⁶ are not all simultaneously N;    -   X⁷ is N or CR^(8a);    -   X is N or CR^(8b);    -   X⁹ is N or CR^(8c);    -   Cy is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- to 14-membered        heteroaryl, or 4- to 10-membered heterocycloalkyl, each of which        is optionally substituted with 1 to 4 independently selected R⁹        substituents;    -   R¹, R², R³, R⁴, R⁵, R⁶ and R⁹ are each independently selected        from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a),        C(O)NR^(a)R^(a), C(O)OR^(a), C(O)R^(a), OC(O)NR^(a)R^(a),        NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),        NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),        NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),        NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a),        and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹, R², R³,        R⁴, R⁵, R⁶ and R⁹ are each optionally substituted with 1, 2, 3,        or 4 R^(b) substituents;    -   R⁷ is C₁₋₄ alkyl, halo, CN, OH, cyclopropyl, C₂₋₄ alkynyl, C₁₋₄        alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl,        —N(C₁₋₄ alkyl)₂, OR¹¹, NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹,        OC(O)R¹¹, OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,        NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹, C(═NR¹¹)NR¹¹R¹¹,        NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹,        NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and        S(O)₂NR¹¹R¹¹, wherein the C₁₋₄ alkyl, cyclopropyl, C₂₋₄ alkynyl        and C₁₋₄ alkoxy of R⁷ are each optionally substituted with 1 or        2 halo, OH, CN or OCH₃ substituents and each R¹¹ is        independently selected from H and C₁₋₄ alkyl optionally        substituted with 1 or 2 halo, OH, CN or OCH₃;    -   R^(8a), R^(8b) and R^(8c) are each independently selected from        H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        halo, CN, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂,        —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, OR¹⁰, NHOR¹⁰, C(O)R¹⁰,        C(O)NR¹⁰R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰, OC(O)NR¹⁰R¹⁰, NR¹⁰C(O)R¹⁰,        NR¹⁰C(O)OR¹⁰, NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰, C(═NR¹⁰)NR¹⁰R¹⁰,        NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰,        NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and        S(O)₂NR¹⁰R¹⁰, wherein each R¹⁰ is independently H or C₁₋₄ alkyl        optionally substituted with 1 or 2 groups independently selected        from halo, OH, CN and C₁₋₄ alkoxy and wherein the C₁₋₄ alkyl,        C₃₋₆ cycloalkyl, C₂₋₄ alkenyl and C₂₋₄ alkynyl of R⁸ are each        optionally substituted with 1 or 2 substituents independently        selected from halo, OH, CN, C₁₋₄ alkyl and C₁₋₄ alkoxy;    -   or two adjacent R⁹ substituents together with the carbon atoms        to which they are attached, form a fused phenyl ring, a fused 5-        to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered        heteroaryl ring or a fused C₃₋₁₀ cycloalkyl ring, wherein the        fused 5- to 7-membered heterocycloalkyl ring and fused 5- or        6-membered heteroaryl ring each have 1-4 heteroatoms as ring        members selected from N, O and S and wherein the fused phenyl        ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or        6-membered heteroaryl ring and fused C₃₋₁₀ cycloalkyl ring are        each optionally substituted with 1 or 2 independently selected        R^(b) substituents or 1 or 2 independently selected R^(q)        substituents;    -   each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,        C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(d) substituents;    -   each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄        haloalkyl, halo, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, CN, NH₂,        NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e),        C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e),        NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),        C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e),        S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e),        NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), wherein the C₁₋₄        alkyl, C₃₋₁₀ cycloalkyl, phenyl, 5- or 6-membered heteroaryl and        4-10 membered heterocycloalkyl of R^(d) are each further        optionally substituted with 1-3 independently selected R^(q)        substituents;    -   each R^(b) substituent is independently selected from halo, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c),        OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),        OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),        NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c),        NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),        NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c),        S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c);        wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀        aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each further        optionally substituted with 1-3 independently selected R^(d)        substituents;    -   each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(f) substituents        independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g),        C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),        NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),        NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),        NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g),        S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and        S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(n) substituents        independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo,        CN, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),        C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),        NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),        C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),        S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),        NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o);    -   each R^(g) is independently selected from H, C₁₋₆ alkyl,        C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionally        substituted with 1-3 independently selected R^(p) substituents;    -   or any two R^(a) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or        10-membered heterocycloalkyl group optionally substituted with        1, 2 or 3 R^(h) substituents independently selected from C₁₋₆        alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-6 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,        (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered        heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),        C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i),        NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i),        NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),        NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i),        S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and        S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h)        are each further optionally substituted by 1, 2, or 3 R^(j)        substituents independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀        aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k), SR^(k),        C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),        OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),        NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),        NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k),        S(O)₂R^(k), NRS(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and        S(O)₂NR^(k)R^(k); or two R^(h) groups attached to the same        carbon atom of the 4- to 10-membered heterocycloalkyl taken        together with the carbon atom to which they are attached form a        C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2        heteroatoms as ring members selected from O, N or S;    -   or any two R^(c) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(e) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(g) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(i) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(k) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(o) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents; and    -   each R^(e), R^(i), R^(k), R^(o) or R^(p) is independently        selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or        6-membered heteroaryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5        or 6-membered heteroaryl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of        R^(e), R^(i), R^(k), R^(o) or R^(p) are each optionally        substituted with 1, 2 or 3 R^(q) substituents;    -   each R^(q) is independently selected from OH, CN, —COOH, NH₂,        halo, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,        phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl,        C₃₋₆ cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄haloalkoxy, wherein the        C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 membered        heterocycloalkyl, and 5-6 membered heteroaryl of R^(q) are each        optionally substituted with halo, OH, CN, —COOH, NH₂, C₁₋₄        alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀        cycloalkyl and 4-6 membered heterocycloalkyl and each R¹² is        independently C₁₋₆ alkyl;    -   provided that R⁷ is other than NH₂, when X⁸ is CR^(8b) and X⁷        and X⁹ are each N; and the compound is other than        (1R,5S,6R)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine        or        (1S,5R,6S)-5-(2,6-difluoro-3-((2-methoxypyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-(fluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine.

In some embodiments of compounds of Formula (I′), Cy is other than3-amino-1-fluoromethyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-1-yl. Incertain instances, when any of R^(8a), R^(8b) or R^(8C) is F, Cy is not3-amino-1-fluoromethyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-1-yl.

In certain instances, when any of R^(8a), R^(8b) or R^(8c) is halo, Cyis not 3-amino-1-fluoromethyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-1-yl.In certain instances, when R⁷ is F, Cy is not3-amino-1-fluoromethyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-1-yl. Incertain instances, when R⁷ is halo, Cy is not3-amino-1-fluoromethyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-1-yl.

In some embodiments of compounds of Formula (I′), Cy is C₆₋₁₀ aryl,optionally substituted with 1 to 4 independently selected R⁹substituents. In certain embodiments, Cy is phenyl or naphthyl, each ofwhich is optionally substituted with 1 to 4 independently selected R⁹substituents. In certain embodiments, Cy is phenyl optionallysubstituted with 1 to 4 independently selected R⁹ substituents. Incertain embodiments, Cy is unsubstituted phenyl.

In some embodiments of compounds of Formula (I′), Cy is C₃₋₁₀cycloalkyl, optionally substituted with 1 to 4 independently selected R⁹substituents. In certain embodiments, Cy is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, each of which isoptionally substituted with 1 to 4 independently selected R⁹substituents.

In some embodiments of compounds of Formula (I′), Cy is 5- to14-membered heteroaryl, optionally substituted with 1 to 4 independentlyselected R⁹ substituents. In certain embodiments, Cy is pyridy,primidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl,azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl,quinolinyl, isoquinolinyl, naphthyridinyl, indolyl, benzothiophenyl,benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, thienyl,furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl, each of which is optionallysubstituted with 1 to 4 independently selected R⁹ substituents.

In some embodiments of compounds of Formula (I′), Cy is 4- to10-membered heterocycloalkyl, optionally substituted with 1 to 4independently selected R⁹ substituents. In certain embodiments, Cy isazetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl,dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl,pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl,2,3-dihydro-1,4-benzodioxin-6-yl and thiomorpholino, each of which isoptionally substituted with 1 to 4 independently selected R⁹substituents. In some embodiments, Cy is2,3-dihydro-1,4-benzodioxin-6-yl optionally substituted with 1 to 4independently selected R⁹ substituents. In some embodiments, Cy isunsubstituted 2,3-dihydro-1,4-benzodioxin-6-yl.

In some embodiments of compounds of Formula (I′), X⁷ is CR^(8a), X⁸ isCR^(8b) and X⁹ is CR^(8C). In certain instances, R^(8a), R^(8b) andR^(8c) are each H.

In some embodiments of compounds of Formula (I′), X⁷ is CR^(8a), X⁸ is Nand X⁹ is N. In certain instances, R^(8a) is H.

In some embodiments of compounds of Formula (I′), X⁷ is CR^(8a), X⁸ is Nand X⁹ is CR^(8c). In certain instances, R^(8a) and R^(8c) are each H.

In some embodiments of compounds of Formula (I′), X⁷ is CR^(8a), X⁸ isCR^(8b) and X⁹ is N. In certain instances, R^(8a) and R^(8c) are each H.

In some embodiments of compounds of Formula (I′), X⁷ is N, X⁸ is CR^(8b)and X⁹ is CR^(8c). In certain instances, R^(8a) and R^(8c) are each H.

In some embodiments of compounds of Formula (I′), X⁷ is N, X⁸ is N andX⁹ is CR^(8c). In certain instances, R^(8c) is H.

In some embodiments of compounds of Formula (I′), X⁷ is N, X⁸ is CR^(8b)and X⁹ is N. In certain instances, R^(8b) is H.

In some embodiments of compounds of Formula (I′), X⁷, X⁸ and X⁹ are eachN.

In some embodiments, the present disclosure provides compounds ofFormula (I):

-   -   or a pharmaceutically acceptable salt or a stereoisomer thereof,        wherein:    -   X¹ is N or CR¹;    -   X² is N or CR²;    -   X³ is N or CR³;    -   X⁴ is N or CR⁴;    -   X⁵ is N or CR⁵;    -   X⁶ is N or CR⁶;    -   wherein X¹, X² and X³ are not all simultaneously N;    -   wherein X⁴, X⁵ and X⁶ are not all simultaneously N;    -   R¹, R², R³, R⁴, R⁵, R⁶ and R⁹ are each independently selected        from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a),        C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),        NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),        NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),        NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),        NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a),        and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹, R², R³,        R⁴, R⁵, R⁶ and R⁹ are each optionally substituted with 1, 2, 3,        or 4 R^(b) substituents;    -   R⁷ is C₁₋₄ alkyl, halo, CN, OH, cyclopropyl, C₂₋₄ alkynyl, C₁₋₄        alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl,        —N(C₁₋₄ alkyl)₂, OR¹¹, NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹,        OC(O)R¹¹, OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,        NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹, C(═NR¹¹)NR¹¹R¹¹,        NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹,        NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and        S(O)₂NR¹¹R¹¹, wherein the C₁₋₄ alkyl, cyclopropyl, C₂₋₄ alkynyl        and C₁₋₄ alkoxy of R⁷ are each optionally substituted with 1 or        2 halo, OH, CN or OCH₃ substituents and each R¹¹ is        independently selected from H and C₁₋₄ alkyl optionally        substituted with 1 or 2 halo, OH, CN or OCH₃;    -   each R⁸ is independently selected from H, C₁₋₄ alkyl, C₃₋₆        cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, CN, OH, C₁₋₄        alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl,        —N(C₁₋₄ alkyl)₂, OR¹⁰, NHOR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹⁰, C(O)OR¹⁰,        OC(O)R¹⁰, OC(O)NR¹⁰R¹⁰, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)OR¹⁰,        NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰, C(═NR¹⁰)NR¹⁰R¹⁰,        NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰,        NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and        S(O)₂NR¹⁰R¹⁰, wherein each R¹⁰ is independently H or C₁₋₄ alkyl        optionally substituted with 1 or 2 groups independently selected        from halo, OH, CN and C₁₋₄ alkoxy and wherein the C₁₋₄ alkyl,        C₃₋₆ cycloalkyl, C₂₋₄ alkenyl and C₂₋₄ alkynyl of R⁸ are each        optionally substituted with 1 or 2 substituents independently        selected from halo, OH, CN, C₁₋₄ alkyl and C₁₋₄ alkoxy;    -   or two adjacent R⁹ substituents together with the carbon atoms        to which they are attached, form a fused phenyl ring, a fused 5-        to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered        heteroaryl ring or a fused C₃₋₁₀ cycloalkyl ring, wherein the        fused 5- to 7-membered heterocycloalkyl ring and fused 5- or        6-membered heteroaryl ring each have 1-4 heteroatoms as ring        members selected from N, O and S and wherein the fused phenyl        ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or        6-membered heteroaryl ring and fused C₃₋₁₀ cycloalkyl ring are        each optionally substituted with 1 or 2 independently selected        R^(q) substituents or 1 or 2 independently selected R^(b)        substituents;    -   each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,        C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(d) substituents;    -   each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄        haloalkyl, halo, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, CN, NH₂,        NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e),        C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e),        NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),        C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e),        S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e),        NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), wherein the C₁₋₄        alkyl, C₃₋₁₀ cycloalkyl, phenyl, 5- or 6-membered heteroaryl and        4-10 membered heterocycloalkyl of R^(d) are each further        optionally substituted with 1-3 independently selected R^(q)        substituents;    -   each R^(b) substituent is independently selected from halo, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c),        OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),        OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),        NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c),        NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c),        NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c),        S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c);        wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀        aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each further        optionally substituted with 1-3 independently selected R^(d)        substituents;    -   each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(f) substituents        independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g),        C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),        NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),        NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),        NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g),        S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and        S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(n) substituents        independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo,        CN, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),        C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),        NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),        C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),        S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),        NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o);    -   each R^(g) is independently selected from H, C₁₋₆ alkyl,        C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionally        substituted with 1-3 independently selected R^(p) substituents;    -   or any two R^(a) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or        10-membered heterocycloalkyl group optionally substituted with        1, 2 or 3 R^(h) substituents independently selected from C₁₋₆        alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-6 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,        (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered        heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),        C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i),        NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i),        NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),        NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i),        S(O)₂R^(i), NR'S(O)₂R^(i), NR'S(O)₂NR^(i)R^(i), and        S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h)        are each further optionally substituted by 1, 2, or 3 R^(j)        substituents independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀        aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k), SR^(k),        C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),        C(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),        NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),        NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k),        S(O)₂R^(k), NRS(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and        S(O)₂NR^(k)R^(k); or two R^(h) groups attached to the same        carbon atom of the 4- to 10-membered heterocycloalkyl taken        together with the carbon atom to which they are attached form a        C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2        heteroatoms as ring members selected from O, N or S;    -   or any two R^(c) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(e) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(g) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(i) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(k) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(o) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents; and    -   each R^(e), R^(i), R^(k), R^(o) or R^(p) is independently        selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or        6-membered heteroaryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5        or 6-membered heteroaryl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of        R^(e), R^(i), R^(k), R^(o) or R^(p) are each optionally        substituted with 1, 2 or 3 R^(q) substituents;    -   each R^(q) is independently selected from OH, CN, —COOH, NH₂,        halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, phenyl, 4- to        6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, C₃₋₆        cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄ haloalkoxy, wherein the        C₁₋₄ alkyl, phenyl, 4- to 6-membered heterocycloalkyl and 5- or        6-membered heteroaryl of R^(q) are each optionally substituted        with 1 or 2 substituents independently selected from halo, OH,        CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₁₀ cycloalkyl and        4-, 5-, or 6-membered heterocycloalkyl and each R¹² is        independently C₁₋₆ alkyl;    -   the subscript n is an integer of 1, 2, 3, 4 or 5; and    -   the subscript m is an integer of 1, 2 or 3.

In some embodiments, the present disclosure provides compounds ofFormula (I):

-   -   or a pharmaceutically acceptable salt or a stereoisomer thereof,        wherein:    -   X¹ is N or CR¹;    -   X² is N or CR²;    -   X³ is N or CR³;    -   X⁴ is N or CR⁴;    -   X⁵ is N or CR⁵;    -   X⁶ is N or CR⁶    -   wherein X¹, X² and X³ are not all simultaneously N;    -   wherein X⁴, X⁵ and X⁶ are not all simultaneously N;    -   R¹, R², R³, R⁴, R⁵, R⁶ and R⁹ are each independently selected        from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a),        C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),        NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),        NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),        NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),        NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a),        and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀        cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,        and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹, R², R³,        R⁴, R⁵, R⁶ and R⁹ are each optionally substituted with 1, 2, 3,        or 4 R^(b) substituents;    -   R⁷ is C₁₋₄ alkyl, halo, CN, OH, cyclopropyl, C₂₋₄ alkynyl, C₁₋₄        alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl,        —N(C₁₋₄ alkyl)₂, OR¹¹, NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹,        OC(O)R¹¹, OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,        NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹, C(═NR¹¹)NR¹¹R¹¹,        NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹,        NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and        S(O)₂NR¹¹R¹¹, wherein each R¹¹ is independently selected from H        and C₁₋₄ alkyl optionally substituted with 1 or 2 halo, OH, CN        or OCH₃;    -   each R⁸ is independently selected from H, C₁₋₄ alkyl, C₃₋₆        cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, CN, OH, C₁₋₄        alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl,        —N(C₁₋₄ alkyl)₂, OR¹⁰, NHOR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹⁰, C(O)OR¹⁰,        OC(O)R¹⁰, OC(O)NR¹⁰R¹⁰, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)OR¹⁰,        NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰, C(═NR¹⁰)NR¹⁰R¹⁰,        NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰,        NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and        S(O)₂NR¹⁰R¹⁰, wherein each R¹⁰ is independently H or C₁₋₄ alkyl        optionally substituted with 1 or 2 groups independently selected        from halo, OH, CN and C₁₋₄ alkoxy and wherein the C₁₋₄ alkyl,        C₃₋₆ cycloalkyl, C₂₋₄ alkenyl and C₂₋₄ alkynyl of R⁸ are each        optionally substituted with 1 or 2 substituents independently        selected from halo, OH, CN, C₁₋₄ alkyl and C₁₋₄ alkoxy;    -   or two adjacent R⁹ substituents together with the carbon atoms        to which they are attached, form a fused phenyl ring, a fused 5-        to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered        heteroaryl ring or a fused C₃₋₁₀ cycloalkyl ring, wherein the        fused 5- to 7-membered heterocycloalkyl ring and fused 5- or        6-membered heteroaryl ring each have 1-4 heteroatoms as ring        members selected from N, O and S and wherein the fused phenyl        ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or        6-membered heteroaryl ring and fused C₃₋₁₀ cycloalkyl ring are        each optionally substituted with 1 or 2 independently selected        R^(q) substituents;    -   each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,        C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(d) substituents;    -   each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄        haloalkyl, halo, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, CN, NH₂,        NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e),        C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e),        NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),        C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e),        S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e),        NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), wherein the C₁₋₄        alkyl, C₃₋₁₀ cycloalkyl, phenyl, 5- or 6-membered heteroaryl and        4-10 membered heterocycloalkyl of R^(d) are each further        optionally substituted with 1-3 independently selected R^(q)        substituents;    -   each R^(b) substituent is independently selected from halo, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c),        OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),        OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR)NR^(c)R^(c),        NR^(c)C(═NR)NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),        NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),        NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c),        S(O)NR^(c)R^(c), S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the        C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each further        optionally substituted with 1-3 independently selected R^(d)        substituents;    -   each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(f) substituents        independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄        alkyl-, halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g),        C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),        NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),        NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),        NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g),        S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and        S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl-, and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(n) substituents        independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo,        CN, R^(o), NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o),        C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o),        NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),        C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),        S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),        NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o);    -   each R^(g) is independently selected from H, C₁₋₆ alkyl,        C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionally        substituted with 1-3 independently selected R^(p) substituents;    -   or any two R^(a) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or        10-membered heterocycloalkyl group optionally substituted with        1, 2 or 3 R^(h) substituents independently selected from C₁₋₆        alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-6 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,        (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 membered        heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, halo, CN, OR^(k), SR^(k), NHOR^(k), C(O)R^(k),        C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k),        NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k),        NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),        NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k),        S(O)₂R^(k), NR^(k)S(O)₂R^(k), NR'S(O)₂NR^(k)R^(k), and        S(O)₂NR^(k)R^(k), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄        alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h)        are each further optionally substituted by 1, 2, or 3 R^(j)        substituents independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀        aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k), SR^(k),        C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),        OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),        NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),        NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k),        S(O)₂R^(k), NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and        S(O)₂NR^(k)R^(k); or two R^(h) groups attached to the same        carbon atom of the 4- to 10-membered heterocycloalkyl taken        together with the carbon atom to which they are attached form a        C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2        heteroatoms as ring members selected from O, N or S;    -   or any two R^(c) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(e) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(g) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(i) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(k) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;    -   or any two R^(o) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents; and    -   each R^(e), R^(i), R^(k), R^(o) or R^(p) is independently        selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or        6-membered heteroaryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄        alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5        or 6-membered heteroaryl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of        R^(e), R^(i), R^(k), R^(o) or R^(p) are each optionally        substituted with 1, 2 or 3 R^(q) substituents;    -   each R^(q) is independently selected from OH, CN, —COOH, NH₂,        halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, phenyl, 4- to        6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, C₃₋₆        cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄ haloalkoxy, wherein the        C₁₋₄ alkyl, phenyl, 4- to 6-membered heterocycloalkyl and 5- or        6-membered heteroaryl of R^(q) are each optionally substituted        with 1 or 2 substituents independently selected from halo, OH,        CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₁₀ cycloalkyl and        4-, 5-, or 6-membered heterocycloalkyl and each R¹² is        independently C₁₋₆ alkyl;    -   the subscript n is an integer of 1, 2, 3, 4 or 5; and    -   the subscript m is an integer of 1, 2 or 3.

The compounds, or pharmaceutically acceptable salts or stereoisomersthereof, as described herein are useful as inhibitors of the PD-1/PD-L1protein/protein interaction. For example, compounds or pharmaceuticallyacceptable salts or stereoisomers thereof as described herein candisrupt the PD-1/PD-L1 protein/protein interaction in the PD-1 pathway.

In some embodiments, the present disclosure provides compounds havingFormula (II):

or a pharmaceutically acceptable salt or a stereoisomer thereof. Incertain embodiments of compounds of Formula (II), R² is halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R² are each optionally substituted with1, 2, 3, or 4 R^(b) substituents. Other variables of Formula (II) are asdefined in Formula (I) or any embodiment of compounds of Formula (I) asdescribed herein. In one embodiment of compounds of Formula (II), R⁷ isCN or C₁₋₄ alkyl optionally substituted with R^(q). In anotherembodiment, R⁷ is CH₃ or CN.

In some embodiments, the present disclosure provides compounds havingFormula

or a pharmaceutically acceptable salt or a stereoisomer thereof. Incertain embodiments of compounds of Formula (III), R² is halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R² are each optionally substituted with1, 2, 3, or 4 R^(b) substituents. Other variables of Formula (III) areas defined in Formula (I) or any embodiment of compounds of Formula (I)as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (IV):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (IV) are as defined in Formula (I) or anyembodiment of compounds of Formula (I) as described herein. In certainembodiments of compounds of Formula (II), R² is halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R² are each optionally substituted with1, 2, 3, or 4 R^(b) substituents.

In some embodiments, the present disclosure provides compounds havingFormula (V):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (V) are as defined in Formula (I) or anyembodiment of compounds of Formula (I) as described herein. In certainembodiments of compounds of Formula (V), R² is halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R² are each optionally substituted with1, 2, 3, or 4 R^(b) substituents.

In some embodiments, the present disclosure provides compounds havingFormula (VI):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (VI) are as defined in Formula (I) or anyembodiment of compounds of Formula (I) as described herein. In certainembodiments of compounds of Formula (VI), R² is halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R² are each optionally substituted with1, 2, 3, or 4 R^(b) substituents.

In some embodiments, the present disclosure provides compounds havingFormula (VII):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (VII) are as defined in Formula (I′) or (I) orany embodiment of compounds of Formula (I′) or (I) as described herein.In certain embodiments of compounds of Formula (VII), is halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R¹ are each optionally substituted with1, 2, 3, or 4 R^(b) substituents.

In some embodiments, the present disclosure provides compounds havingFormula (VIII):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (VIII) are as defined in Formula (I′) or (I) orany embodiment of compounds of Formula (I′) or (I) as described herein.In certain instances, R⁹ is H, n is 1, X⁷ is CR^(8a), X⁸ is CR^(8b) andX⁹ is CR^(8c). In some instances, X⁷, X⁸ and X⁹ are each CH.

In some embodiments, the present disclosure provides compounds havingFormula (IX):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (IX) are as defined in Formula (I′) or (I) orany embodiment of compounds of Formula (I′) or (I) as described herein.In certain instances, R⁹ is H, n is 1, X⁷ is CR^(8a), X⁸ is CR^(8b) andX⁹ is CR^(8c). In some instances, X⁷, X⁸ and X⁹ are each CH.

In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI,or a pharmaceutically acceptable salt or a stereoisomer thereof, themoiety

is selected from:

wherein the substituents R¹, R², R³, R⁴, R⁵ and R⁶ are as defined inFormula (I′), (I) or any embodiment of compounds of Formula (I′) or (I)as described herein. In certain embodiments, at each occurrence, R¹, R³,R⁴, R⁵ and R⁶ are each H.

In some embodiments of compounds of Formula I′, I, VII, VIII, or IX, ora pharmaceutically acceptable salt or a stereoisomer thereof, the moiety

is selected from:

wherein the substituents R¹, R², R³, R⁴, R⁵ and R⁶ are as defined inFormula (I′), (I) or any embodiment of compounds of Formula (I′), (I) asdescribed herein. In certain embodiments, at each occurrence, R¹, R²,R⁴, R⁵ and R⁶ are each H.

In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI,or a pharmaceutically acceptable salt or a stereoisomer thereof, X¹ isCR¹, X³ is CR³, X⁴ is CR⁴, X⁵ is CR⁵ and X⁶ is CR⁶. In some instances,X¹, X³, X⁴, X⁵ and X⁶ are each CH. In one embodiment, X² is CR².

In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI,or a pharmaceutically acceptable salt or a stereoisomer thereof, X¹ isCR¹, X³ is CR³, X⁴ is CR⁴, X⁵ is CR⁵ and X⁶ is N. In some instances, X¹,X³, X⁴ and X⁵ are each CH. In one embodiment, X² is CR².

In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI,or a pharmaceutically acceptable salt or a stereoisomer thereof, X¹ isCR¹, X³ is CR³, X⁴ is N, X⁵ is CR⁵ and X⁶ is N. In some instances, X¹,X³ and X⁵ are each CH. In one embodiment, X² is CR².

In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI,or a pharmaceutically acceptable salt or a stereoisomer thereof, X¹ isCR¹, X³ is N, X⁴ is CR⁴, X⁵ is CR⁵ and X⁶ is N. In some instances, X¹,X⁴ and X⁵ are each CH. In one embodiment, X² is CR².

In some embodiments of compounds of Formula I′, I, VII, VIII, or IX, ora pharmaceutically acceptable salt or a stereoisomer thereof, X¹ is CR¹,X² is N, X⁴ is CR⁴, X⁵ is CR⁵ and X⁶ is CR⁶. In some instances, X¹, X⁴,X⁵ and X⁶ are each CH. In one embodiment, X² is CR².

In some embodiments of compounds of Formula I′, I, VII, VIII, or IX, ora pharmaceutically acceptable salt or a stereoisomer thereof, X¹ is CR¹,X² is CR², X⁴ is CR⁴, X⁵ is CR⁵ and X⁶ is CR⁶. In some instances, X¹,X², X⁴, X⁵ and X⁶ are each CH. In one embodiment, X³ is CR³.

In some embodiments of compounds of Formula I′, I, VII, VIII, or IX, ora pharmaceutically acceptable salt or a stereoisomer thereof, X¹ is CR¹,X² is CR², X⁴ is CR⁴, X⁵ is CR⁵ and X⁶ is N. In some instances, X¹, X²,X⁴ and X⁵ are each CH. In one embodiment, X³ is CR³.

In some embodiments of compounds of Formula I′, I, VII, VIII, or IX, ora pharmaceutically acceptable salt or a stereoisomer thereof, X¹ is CR¹,X² is CR², X⁴ is N, X⁵ is CR⁵ and X⁶ is N. In some instances, X¹, X² andX⁵ are each CH. In one embodiment, X³ is CR³.

In some embodiments of compounds of Formula I′, I, VII, VIII, or IX, ora pharmaceutically acceptable salt or a stereoisomer thereof, X¹ is CR¹,X² is N, X⁴ is CR⁴, X⁵ is CR⁵ and X⁶ is N. In some instances, X¹, X⁴ andX⁵ are each CH. In one embodiment, X³ is CR³.

In some embodiments of compounds of Formula I′, I, VII, VIII, or IX, ora pharmaceutically acceptable salt or a stereoisomer thereof, X¹ is CR¹,X² is N, X⁴ is CR⁴, X⁵ is CR⁵ and X⁶ is CR⁶. In some instances, X¹, X⁴,X⁵ and X⁶ are each CH. In one embodiment, X³ is CR³.

In some embodiments, R¹, R³, R⁴, R⁵ and R⁶, are each independentlyselected from H, C₁₋₆ alkyl, CN, —N(C₁₋₆ alkyl)₂ and halo.

In some embodiments, R¹, R³, R⁴, R⁵ and R⁶, are each independentlyselected from H, CN, C₁₋₆ alkyl and halo.

In some embodiments, R¹, R², R⁴, R⁵ and R⁶, are each independentlyselected from H, C₁₋₆ alkyl, CN, —N(C₁₋₆ alkyl)₂ and halo.

In some embodiments, R¹, R², R⁴, R⁵ and R⁶, are each independentlyselected from H, CN, C₁₋₆ alkyl and halo.

In some embodiments, R¹, R², R³, R⁴, R⁵, R⁸ and R⁹ are each H.

In some embodiments, R¹, R³, R⁴, R⁵, R⁶, R⁸ and R⁹ are each H.

In some embodiments, R¹, R², R⁴, R⁵, R⁶, R⁸ and R⁹ are each H.

In some embodiments, R² is —CH₂—R^(b).

In some embodiments, R³ is —CH₂—R^(b).

In some embodiments, R³ is H, halo or C₁₋₆alkyl.

In some embodiments, R³ is H, Cl or OCH₃.

In some embodiments, two adjacent R⁹ substituents on the phenyl ringtaken together with the carbon atoms to which they are attached form a5-, 6- or 7-membered fused heterocycloalkyl optionally substituted by 1or 2 R^(q) substituents. In some instances, the fused heterocycloalkylis fused dioxanyl optionally substituted with 1 or 2 R^(q) substituents.In certain instances, the fused heterocycloalkyl has carbon and 1 or 2heteroatoms as ring members selected from O, N or S, wherein the carbonring atom is optionally oxidized to form carbonyl, the N ring atom isoptionally oxidized to form NO and the S ring atom is optionallyoxidized to form SO or SO₂.

In some embodiments, the subscript n is 2 and the subscript m is 1.

In some embodiments, R⁷ is C₁₋₄ alkyl or CN.

In some embodiments, R⁷ is CH₃ or CN.

In some embodiments, R⁸ and R⁹ are each H.

In some embodiments of compounds of Formula I′, I, II, III, III, IV, V,VI, VII, VIII, or IX, R² is C₁₋₄ alkyl substituted with R^(b). Incertain embodiments, R^(b) is NHR^(c) or NR^(c)R^(c). In certainembodiments, R^(b) is NR^(c)R^(c). In other embodiments, R^(b) is2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino,2-carboxypiperidin-1-yl, (cyanomethyl)amino,(S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or2-carboxypiperidin-1-yl, each of which is optionally substituted with 1,2 or 3 R^(q) substituents. In other embodiments, R^(b) is2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino,2-carboxypiperidin-1-yl, (cyanomethyl)amino,(S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or2-carboxypiperidin-1-yl. In other embodiments, R^(b) is2-hydroxyethylamino. In other embodiments, R^(b) is2-carboxypiperidin-1-yl. In other embodiments, R² is C₁₋₄ alkylsubstituted with R^(q).

In some embodiments compounds of Formula I′, I, II, III, III, IV, V, VI,VII, VIII, or IX, R² is C₁₋₄ alkoxy substituted with R^(d). In certainembodiments, R^(d) is phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl,4-pyridyl, each of which is optionally substituted with 1, 2 or 3 R^(q)substituents.

In some embodiments compounds of Formula I′, I, II, III, III, IV, V, VI,VII, VIII, or IX, R² is —OCH₂R^(d). In certain embodiments, R^(d) isphenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, 4-pyridyl, each of which isoptionally substituted with 1, 2 or 3 R^(q) substituents.

In some embodiments of compounds of Formula I′, I, II, III, IV, V, orVI, VII, VIII, or IX, R³ is C₁₋₄ alkyl substituted with R^(b). Incertain embodiments, R^(b) is NHR^(c) or NR^(c)R^(c). In certainembodiments, R^(b) is NR^(c)R^(c). In other embodiments, R^(b) is2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino,2-carboxypiperidin-1-yl, (cyanomethyl)amino,(S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or2-carboxypiperidin-1-yl, each of which is optionally substituted with 1,2 or 3 R^(q) substituents. In other embodiments, R^(b) is2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino,2-carboxypiperidin-1-yl, (cyanomethyl)amino,(S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or2-carboxypiperidin-1-yl. In other embodiments, R^(b) is2-hydroxyethylamino. In other embodiments, R^(b) is2-carboxypiperidin-1-yl. In other embodiments, R³ is C₁₋₄ alkylsubstituted with R^(q).

In some embodiments of compounds of Formula I′, I, II, III, III, IV, V,VI, VII, VIII, or IX, R³ is C₁₋₄ alkoxy substituted with R^(d). Incertain embodiments, R^(d) is phenyl, 3-cyanophenyl, 3-pyridyl,2-pyridyl, 4-pyridyl, each of which is optionally substituted with 1, 2or 3 R^(q) substituents.

In some embodiments of compounds of Formula I′, I, II, III, III, IV, V,VI, VII, VIII, or IX, R³ is —OCH₂R^(d). In certain embodiments, R^(d) isphenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, 4-pyridyl, each of which isoptionally substituted with 1, 2 or 3 R^(q) substituents.

In some embodiments of compounds of Formula I′, I, II, III, IV, V, VI,VII, VIII, or IX, R³ is 2-hydroxyethylaminomethyl,2-hydroxyethyl(methyl)aminomethyl, 2-carboxypiperidin-1-ylmethyl,(cyanomethyl)aminomethyl, (S)-2-carboxypiperidin-1-ylmethyl,(R)-2-carboxypiperidin-1-ylmethyl, 2-carboxypiperidin-1-ylmethyl,benzyloxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy,2-pyridylmethoxy, 3-pyridylmethoxy, or 4-pyridylmethoxy, each of whichis optionally substituted with 1, 2 or 3 R^(q) substituents. In certainembodiments, R³ is 2-hydroxyethylaminomethyl,2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl,(R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy, each of whichis optionally substituted with 1, 2 or 3 R^(q) substituents.

In some embodiments of compounds of Formula I, II, III, V, or VII, R⁸ isH, halo, CN, N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl or C₁₋₆ alkoxy, wherein the C₁₋₆alkyl and C₁₋₆ alkoxy are each optionally substituted with 1-3 R^(q)substituents. In some embodiments of compounds of Formula I′, VIII, orIX, R^(8a), R^(8b) and R^(8c) are each independently selected from H,halo, CN, N(C₁₋₆ alkyl)₂, C₁₋₆ alkyl and C₁₋₆ alkoxy, wherein the C₁₋₆alkyl and C₁₋₆ alkoxy are each optionally substituted with 1-3 R^(q)substituents.

In some embodiments of compounds of Formula I, II, III, V or VII, R⁸ isH, halo, CN, N(CH₃)₂ or CH₃. In some embodiments of compounds of FormulaI′, VIII, or IX, R^(8a), R^(8b) and R^(8c) are each independentlyselected from H, halo, CN, N(CH₃)₂ and CH₃.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds offormula (I′) or (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)-includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl,” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl,” refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl,” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl,” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene,” employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.

The term “alkoxy,” employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “alkylthio,” employed alone or in combination with other terms,refers to a group of formula —S-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkylthio” refers to an alkylthiogroup, the alkyl group of which has n to m carbons. Example alkylthiogroups include methylthio, ethylthio, etc. In some embodiments, thealkyl group of the alkylthio group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “amino,” employed alone or in combination with other terms,refers to a group of formula —NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl,” employed alone or in combination with other terms,refers to an alkyl group in which one or more of the hydrogen atoms hasbeen replaced by a halogen atom. The term “C_(n-m) haloalkyl” refers toa C_(n-m) alkyl group having n to m carbon atoms and from at least oneup to {2(n to m)+1} halogen atoms, which may either be the same ordifferent. In some embodiments, the halogen atoms are fluoro atoms. Insome embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅ andthe like. In some embodiments, the haloalkyl group is a fluoroalkylgroup.

The term “haloalkoxy,” employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, indanyl, indenyl and the like. In someembodiments, aryl groups have from 6 to about 10 carbon atoms. In someembodiments aryl groups have 6 carbon atoms. In some embodiments arylgroups have 10 carbon atoms. In some embodiments, the aryl group isphenyl. In some embodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl,quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-,1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine), indolyl,benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl,purinyl, and the like.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur oxygen and phosphorus, and which has 4-10ring members, 4-7 ring members, or 4-6 ring members. Included within theterm “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orbicyclic (e.g., having two fused or bridged rings) ring systems. In someembodiments, the heterocycloalkyl group is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur andoxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkylgroup can be optionally oxidized to form an oxo or sulfido group orother oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.)or a nitrogen atom can be quaternized. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the heterocycloalkyl ring, e.g.,benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. Examples of heterocycloalkyl groups include azetidinyl,azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl,morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl,pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, andthiomorpholino.

The term “arylalkyl,” employed alone or in combination with other terms,refers to an aryl-(alkylene)- group where aryl and alkylene are asdefined herein. An example arylalkyl group is benzyl.

The term “heteroarylalkyl,” employed alone or in combination with otherterms, refers to an heteroaryl-(alkylene)- group, where heteroaryl andalkylene are as defined herein. An example heteroarylalkyl group ispyridylmethyl.

The term “cycloalkylalkyl,” employed alone or in combination with otherterms, refers to a cycloalkyl-(alkylene)- group, where cycloalkyl andalkylene are as defined herein. An example cycloalkylalkyl group iscyclopropylmethyl.

The term “heterocycloalkylalkyl,” employed alone or in combination withother terms, refers to a heterocycloalkyl-(alkylene)- group, whereheterocycloalkyl and alkylene are as defined herein. An exampleheterocycloalkylalkyl group is azetidinylmethyl.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as 3-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., JPharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of the invention of formula 8 can be synthesized using aprocess shown in Scheme 1. In Scheme 1, a suitable halo(Hal¹)-substituted aromatic amine 1 can react with a suitable couplingreagent 2 (where M is, e.g., —B(OH)₂) to produce compound 3 understandard metal catalyzed cross-coupling reaction conditions (such asSuzuki coupling reaction, e.g., in the presence of a palladium catalyst(e.g., 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and abase (e.g., a bicarbonate or a carbonate base)). Then the aromatic amine3 can selectively react with the halo group (Hal²) of compound 4 undersuitable S_(N)Ar conditions (such as acid catalyzed, e.g., in thepresence of HCl; or uncatalyzed) or standard coupling reactionconditions (such as Buchwald-Hartwig amination, e.g., in the presence ofa palladium catalyst (e.g.,[(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate) and a base (e.g., a carbonate or butoxide base))forming compound 5. The compound of formula 6 can be synthesized bycoupling the halo group (Hal³) of 5 with a vinyl reagent (e.g., vinylboronic acid pinacol ester) under standard coupling reaction conditions(such as Suzuki coupling reaction, e.g., in the presence of a palladiumcatalyst (e.g.,1,1′-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II)) and abase (e.g., a bicarbonate or a carbonate base)). The vinyl group incompound 6 can be oxidatively cleaved to afford an aldehyde of formula 7in the presence of suitable reagents such as, but not limited to, OsO₄and NaIO₄. Then the compounds of formula 8 can be obtained by areductive amination between the compound of formula 7 and amineHN(R^(c))₂ in an appropriate solvent such as THF or DCM using a reducingagent such as, but not limited to, sodium triacetoxyborohydride,optionally in the presence of a base such as DIPEA.

Compounds of the invention of formula 8 can be alternatively synthesizedusing a process shown in Scheme 2. The aromatic amine 3 can react withthe halo (Hal⁴) of formula 9 under standard coupling reaction conditions(such as Buchwald-Hartwig amination, e.g., in the presence of apalladium catalyst (e.g.,[(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate) and a base (e.g., a carbonate or butoxide base)).Subsequent reduction of the carboxylic acid group in compound 10 cangive an alcohol of formula 11 using a suitable reducing agent such as,but not limited to, lithium aluminum hydride. The alcohol unit incompound 11 can be oxidized to give the aldehyde 7 with a suitableoxidant such as, but not limited to, Dess-Martin periodinane. Then thecompounds of formula 8 can be obtained from compound 7 using similarconditions as shown in Scheme 1.

Compounds of the invention of formula 16 can be synthesized using aprocess shown in Scheme 3. In Scheme 3, the aromatic amine 3 canselectively react with the halo group (Hal⁵) of compound 12 undersuitable S_(N)Ar conditions (acid catalyzed, e.g., in the presence ofHCl; or uncatalyzed) or standard coupling reaction conditions (such asBuchwald-Hartwig amination, e.g., in the presence of a palladiumcatalyst (e.g.,[(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate) and a base (e.g., a carbonate or butoxide base)) togive compound 13. The compound of formula 14 can be synthesized bycoupling the halo group (Hal⁶) of 13 with a vinyl reagent (e.g., vinylboronic acid pinacol ester) under standard coupling reaction conditions(such as Suzuki coupling reaction, e.g., in the presence of a palladiumcatalyst (e.g.,1,1′-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II)) and abase (e.g., a bicarbonate or a carbonate base)). The vinyl group incompound 14 can be oxidatively cleaved to afford an aldehyde of formula15 in the presence of suitable reagents such as, but not limited to,OsO₄ and NaIO₄. Then the compounds of formula 16 can be obtained by areductive amination between the compound of formula 15 and amineHN(R^(c))₂ in a proper solvent such as THF or DCM using a reducing agentsuch as, but not limited to, sodium triacetoxyborohydride, optionally inthe presence of a base such as DIPEA.

Compounds of Formula 21 can be prepared using procedures as outlined inScheme 4. The aromatic amines of Formula 17 can selectively react withthe halo group (Hal⁷) of compound 18 under suitable S_(N)Ar conditions(acid catalyzed, e.g., in the presence of HCl; or uncatalyzed) orsuitable selective coupling reaction conditions (such asBuchwald-Hartwig amination, e.g., in the presence of a palladiumcatalyst (e.g.,[(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate) and a base (e.g., a carbonate or butoxide base)) togive compounds of Formula 19. The halide (Hal⁸) in compounds Formula 19can be coupled to compounds of Formula 20, in which M is a boronic acid,boronic ester or an appropriately substituted metal [e.g., M is B(OR)₂,Sn(Alkyl)₄, or Zn-Hal], under Suzuki coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base) or Stille couplingconditions (e.g., in the presence of a palladium catalyst), or Negishicoupling conditions (e.g., in the presence of a palladium catalyst) togive derivatives of Formula 21. Alternatively, compound Formula 20 canbe a cyclic amine (where M is H and attached to an amine nitrogen inring Cy) and the coupling of aryl halide of Formula 19 with the cyclicamine of Formula 18 can be performed under suitable Buchwald-Hartwigamination conditions (e.g., in the presence of a palladium catalyst anda base such as sodium tert-butoxide).

Alternatively, compounds of Formula 21 can be prepared using reactionsequences as outlined in Scheme 5. Coupling of aromatic halides ofFormula 17 with compounds of Formula 20 can be achieved using similarconditions as described in Scheme 4 (e.g. conditions used for couplingof compounds of Formula 19 with compounds of Formula 20) to givearomatic amines of Formula 22, which can react with the halo group(Hal⁷) of compounds of Formula 18 under suitable S_(N)Ar conditions orsuitable selective coupling reaction conditions as described in Scheme 4to give compounds of Formula 21.

III. Uses of the Compounds

Compounds of the present disclosure can inhibit the activity ofPD-1/PD-L1 protein/protein interaction and, thus, are useful in treatingdiseases and disorders associated with activity of PD-1 and the diseasesand disorders associated with PD-L1 including its interaction with otherproteins such as PD-1 and B7-1 (CD80). In certain embodiments, thecompounds of the present disclosure, or pharmaceutically acceptablesalts or stereoisomers thereof, are useful for therapeuticadministration to enhance immunity in cancer or chronic infection,including enhancement of response to vaccination. In some embodiments,the present disclosure provides a method for inhibiting the PD-1/PD-L1protein/protein interaction. The method includes administering to anindividual or a patient a compound of Formula (I′) or (I) or of any ofthe formulas as described herein, or of a compound as recited in any ofthe claims and described herein, or a pharmaceutically acceptable saltor a stereoisomer thereof. The compounds of the present disclosure canbe used alone, in combination with other agents or therapies or as anadjuvant or neoadjuvant for the treatment of diseases or disorders,including cancer or infection diseases. For the uses described herein,any of the compounds of the disclosure, including any of the embodimentsthereof, may be used.

The compounds of the present disclosure inhibit the PD-1/PD-L1protein/protein interaction, resulting in a PD-1 pathway blockade. Theblockade of PD-1 can enhance the immune response to cancerous cells andinfectious diseases in mammals, including humans. In some embodiments,the present disclosure provides treatment of an individual or a patientin vivo using a compound of Formula (I′) or (I) or a salt orstereoisomer thereof such that growth of cancerous tumors is inhibited.A compound of Formula (I′) or (I) or of any of the formulas as describedherein, or a compound as recited in any of the claims and describedherein, or a salt or stereoisomer thereof, can be used to inhibit thegrowth of cancerous tumors. Alternatively, a compound of Formula (I′) or(I) or of any of the formulas as described herein, or a compound asrecited in any of the claims and described herein, or a salt orstereoisomer thereof, can be used in conjunction with other agents orstandard cancer treatments, as described below. In one embodiment, thepresent disclosure provides a method for inhibiting growth of tumorcells in vitro. The method includes contacting the tumor cells in vitrowith a compound of Formula (I′) or (I) or of any of the formulas asdescribed herein, or of a compound as recited in any of the claims anddescribed herein, or of a salt or stereoisomer thereof. In anotherembodiment, the present disclosure provides a method for inhibitinggrowth of tumor cells in an individual or a patient. The method includesadministering to the individual or patient in need thereof atherapeutically effective amount of a compound of Formula (I′) or (I) orof any of the formulas as described herein, or of a compound as recitedin any of the claims and described herein, or a salt or a stereoisomerthereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I′) or (I) orany of the formulas as described herein, a compound as recited in any ofthe claims and described herein, or a salt thereof. Examples of cancersinclude those whose growth may be inhibited using compounds of thedisclosure and cancers typically responsive to immunotherapy.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers, especiallymetastatic cancers that express PD-L1.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, colon cancer andlung cancer (e.g. non-small cell lung cancer). Additionally, thedisclosure includes refractory or recurrent malignancies whose growthmay be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

PD-1 pathway blockade with compounds of the present disclosure can alsobe used for treating infections such as viral, bacteria, fungus andparasite infections. The present disclosure provides a method fortreating infections such as viral infections. The method includesadministering to a patient in need thereof, a therapeutically effectiveamount of a compound of Formula (I′) or (I) or any of the formulas asdescribed herein, a compound as recited in any of the claims anddescribed herein, a salt thereof. Examples of viruses causing infectionstreatable by methods of the present disclosure include, but are notlimit to, human immunodeficiency virus, human papillomavirus, influenza,hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplexviruses, human cytomegalovirus, severe acute respiratory syndrome virus,ebola virus, and measles virus. In some embodiments, viruses causinginfections treatable by methods of the present disclosure include, butare not limit to, hepatitis (A, B, or C), herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus,influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus,comovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measlesvirus, rubella virus, parvovirus, vaccinia virus, HTLV virus, denguevirus, papillomavirus, molluscum virus, poliovirus, rabies virus, JCvirus and arboviral encephalitis virus.

The present disclosure provides a method for treating bacterialinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula(I′) or (I) or any of the formulas as described herein, a compound asrecited in any of the claims and described herein, or a salt thereof.Non-limiting examples of pathogenic bacteria causing infectionstreatable by methods of the disclosure include Chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, Klebsiella, Proteus, Serratia, Pseudomonas,Legionella, diphtheria, Salmonella, bacilli, cholera, Tetanus, botulism,Anthrax, plague, leptospirosis, and Lyme's disease bacteria.

The present disclosure provides a method for treating fungus infections.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I′) or (I) orany of the formulas as described herein, a compound as recited in any ofthe claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic fungi causing infections treatable by methods ofthe disclosure include Candida (albicans, krusei, glabrata, tropicalis,etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.),Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii,Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioidesimmitis and Histoplasma capsulatum.

The present disclosure provides a method for treating parasiteinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula(I′) or (I) or any of the formulas as described herein, a compound asrecited in any of the claims and described herein, or a salt thereof.Non-limiting examples of pathogenic parasites causing infectionstreatable by methods of the disclosure include Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors for the treatmentof diseases, such as cancer or infections. Examples of cancers includesolid tumors and liquid tumors, such as blood cancers. Examples ofinfections include viral infections, bacterial infections, fungusinfections or parasite infections. For example, the compounds of thepresent disclosure can be combined with one or more inhibitors of thefollowing kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR,PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR,EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer or infections. Non-limiting examples ofinhibitors that can be combined with the compounds of the presentdisclosure for treatment of cancer and infections include an FGFRinhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 andINCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib,baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat andNLG919), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor, a PI3K-gamma inhibitor such asPI3K-gamma selective inhibitor (e.g., INCB50797), a Pim inhibitor, aCSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer),an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors. Exemplary immune checkpointinhibitors include inhibitors against immune checkpoint molecules suchas CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK,PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1and PD-L2. In some embodiments, the immune checkpoint molecule is astimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In someembodiments, the compounds provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab. In some embodiments, the anti PD-1 antibody isSHR-1210.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518 or MK-4166.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562. Insome embodiments, the OX40L fusion protein is MEDI6383.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, oncolytic virotherapy and immunomodulating small molecules,including thalidomide or JAK1/2 inhibitor and the like. The compoundscan be administered in combination with one or more anti-cancer drugs,such as a chemotherapeutics. Example chemotherapeutics include any ofabarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib,busulfan intravenous, busulfan oral, calusterone, capecitabine,carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine,clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin,denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat andzoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab), 4-1BB, antibodies to PD-1 and PD-L1, orantibodies to cytokines (IL-10, TGF-β, etc.). Examples of antibodies toPD-1 and/or PD-L1 that can be combined with compounds of the presentdisclosure for the treatment of cancer or infections such as viral,bacteria, fungus and parasite infections include, but are not limitedto, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

In some embodiments, the anti-cancer agent is an alkylating agent, aproteasome inhibitor, a corticosteroid, or an immunomodulatory agent.Examples of an alkylating agent include cyclophosphamide (CY), melphalan(MEL), and bendamustine. In some embodiments, the proteasome inhibitoris carfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

The compounds of Formula (I′) or (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or salts, stereoisomers thereof can be used in combination with animmune checkpoint inhibitor for the treatment of cancer and viralinfections.

Exemplary immune checkpoint inhibitors include inhibitors against immunecheckpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47,OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137(also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3,TIM3, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immunecheckpoint molecule is a stimulatory checkpoint molecule selected fromCD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, theimmune checkpoint molecule is an inhibitory checkpoint molecule selectedfrom A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, andVISTA. In some embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PDT antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MED14736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518 or MK-4166.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562. Insome embodiments, the OX40L fusion protein is MEDI6383.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The compounds of Formula (I′) or (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or salts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I′) or (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or salts thereof can be used in combination with a vaccination protocolfor the treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I′) or (I) or any of theformulas as described herein, a compound as recited in any of the claimsand described herein, or salts thereof can be combined with dendriticcells immunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

The compounds of Formula (I′) or (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or salts thereof can be used in combination with vaccines, to stimulatethe immune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, Chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, Klebsiella, Proteus, Serratia, Pseudomonas,Legionella, diphtheria, Salmonella, bacilli, cholera, Tetanus, botulism,Anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I′) or (I) or any of the formulas asdescribed herein, a compound as recited in any of the claims anddescribed herein, or a pharmaceutically acceptable salt thereof, or anyof the embodiments thereof, and at least one pharmaceutically acceptablecarrier or excipient. These compositions can be prepared in a mannerwell known in the pharmaceutical art, and can be administered by avariety of routes, depending upon whether local or systemic treatment isindicated and upon the area to be treated. Administration may be topical(including transdermal, epidermal, ophthalmic and to mucous membranesincluding intranasal, vaginal and rectal delivery), pulmonary (e.g., byinhalation or insufflation of powders or aerosols, including bynebulizer; intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel KOOLV™) Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

V. Labeled Compounds and Assay Methods

The compounds of the present disclosure can further be useful ininvestigations of biological processes in normal and abnormal tissues.Thus, another aspect of the present invention relates to labeledcompounds of the invention (radio-labeled, fluorescent-labeled, etc.)that would be useful not only in imaging techniques but also in assays,both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1protein in tissue samples, including human, and for identifying PD-L1ligands by inhibition binding of a labeled compound. Accordingly, thepresent invention includes PD-1/PD-L1 binding assays that contain suchlabeled compounds.

The present invention further includes isotopically-substitutedcompounds of the disclosure. An “isotopically-substituted” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). It is to be understood that a “radio-labeled”compound is a compound that has incorporated at least one isotope thatis radioactive (e.g., radionuclide). Suitable radionuclides that may beincorporated in compounds of the present invention include but are notlimited to ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N,¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵Iand ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro PD-L1 protein labelingand competition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I,¹³¹I, ³⁵S or will generally be most useful. For radio-imagingapplications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br willgenerally be most useful. In some embodiments the radionuclide isselected from the group consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.Synthetic methods for incorporating radio-isotopes into organiccompounds are known in the art.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a PD-L1 protein bymonitoring its concentration variation when contacting with the PD-L1protein, through tracking of the labeling. For example, a test compound(labeled) can be evaluated for its ability to reduce binding of anothercompound which is known to bind to a PD-L1 protein (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the PD-L1 protein directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

VI. Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of PD-L1 including its interaction with other proteins suchas PD-1 and B7-1 (CD80), such as cancer or infections, which include oneor more containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I′) or (I),or any of the embodiments thereof. Such kits can further include one ormore of various conventional pharmaceutical kit components, such as,e.g., containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of PD-1/PD-L1 protein/protein interaction according to atleast one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Open Access Preparative LCMS Purification of some of thecompounds prepared was performed on Waters mass directed fractionationsystems. The basic equipment setup, protocols and control software forthe operation of these systems have been described in detail inliterature. See, e.g., Blom, “Two-Pump At Column Dilution Configurationfor Preparative LC-MS”, K. Blom, J Combi. Chem., 2002, 4, 295-301; Blomet al., “Optimizing Preparative LC-MS Configurations and Methods forParallel Synthesis Purification”, J Combi. Chem., 2003, 5, 670-83; andBlom et al., “Preparative LC-MS Purification: Improved Compound SpecificMethod Optimization”, J Combi. Chem., 2004, 6, 874-883.

Example 12-[({8-[(2-methylbiphenyl-3-yl)amino]quinolin-3-yl}methyl)amino]ethanol

Step 1: 2-methylbiphenyl-3-amine

A mixture of 3-bromo-2-methylaniline (Aldrich, cat #530018: 0.39 mL, 3.2mmol), phenylboronic acid (Aldrich, cat #P20009: 0.50 g, 4.1 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Aldrich,cat #697230: 0.13 g, 0.16 mmol) and potassium carbonate (1.32 g, 9.57mmol) in 1,4-dioxane (20.0 mL) and water (7 mL) was sparged withnitrogen for 5 min. The mixture was then heated and stirred at 110° C.for 1.5 h. The reaction mixture was cooled to room temperature, quenchedwith saturated aqueous NaHCO₃, and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine, dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column eluting withethyl acetate in hexanes (0→15%) to afford the desired product. LC-MScalculated for C₁₃H₁₄N (M+H)⁺: m/z=184.1; found 184.1. ¹H NMR (400 MHz,DMSO) δ 7.40 (dd, J=7.6, 6.8 Hz, 2H), 7.32 (dd, J=7.6, 7.2 Hz, 1H),7.29-7.14 (m, 2H), 6.92 (dd, J=7.6, 7.6 Hz, 1H), 6.64 (d, J=7.2 Hz, 1H),6.40 (d, J=7.2 Hz, 1H), 4.89 (s, 2H), 1.92 (s, 3H).

Step 2: 8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carboxylic acid

To a vial was added racemic2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (Aldrich, cat #481084: 30mg, 0.05 mmol), 2-methylbiphenyl-3-amine (262 mg, 1.43 mmol), ethyl8-bromoquinoline-3-carboxylate (Ark Pharm, cat #AK-47201: 0.200 g, 0.714mmol), bis(dibenzylideneacetone)palladium(0) (Aldrich, cat #227994:0.012 g, 0.021 mmol) and sodium tert-butoxide (Aldrich, cat #359270:96.7 mg, 1.01 mmol). Toluene (3.6 mL) was added and the reaction mixturewas sparged for 5 min with nitrogen then sealed and heated at 130° C.for 18 h. The reaction mixture was cooled, and concentrated in vacuo.The resulting residue was used directly in the next step without furtherpurification. LC-MS calculated for C₂₃H₁₉N₂O₂ (M+H)⁺: m/z=355.1; found355.4.

Step 3: {8-[(2-methylbiphenyl-3-yl)amino]quinolin-3-yl}methanol

To a solution of 8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carboxylicacid (253 mg, 0.714 mmol) in THF (3.6 mL) was added 1.0 M lithiumtetrahydroaluminate in THF (2.14 mL, 2.14 mmol) at −78° C. The resultingmixture was warmed to room temperature, and stirred for 18 h. Themixture was cooled to 0° C. and quenched using the Fieser workup: water(80 μL) was added, followed by 1 N NaOH (240 μL), and then water (80 μL)was added again and the mixture was then stirred for 1 h at roomtemperature. The resulting slurry was diluted with ethyl acetate (10mL), filtered over Celite, and washed with water. The organic extractwas then washed with brine, dried over sodium sulfate, filtered, thenconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (0→40% ethyl acetate/hexanes). LC-MS calculated forC₂₃H₂₁N₂O (M+H)⁺: m/z=341.1; found 341.2.

Step 4: 8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carbaldehyde

To a solution of {8-[(2-methylbiphenyl-3-yl)amino]quinolin-3-yl}methanol(83.0 mg, 0.244 mmol) in methylene chloride (1.0 mL) at 0° C. was addedDess-Martin periodinane (Aldrich, cat #274623: 103 mg, 0.244 mmol). Themixture was stirred for 10 min at 0° C. then quenched at 0° C. withaqueous saturated sodium thiosulfate. The mixture was extracted withmethylene chloride (3×10 mL). The organic extract was then washed withaqueous saturated sodium bicarbonate, water, then brine. The organicextract was dried over sodium sulfate and concentrated in vacuo. Thedesired aldehyde was purified by column chromatography (0 to 20%EtOAc/hexanes). LC-MS calculated for C₂₃H₁₉N₂O (M+H)⁺: m/z=339.1; found339.3.

Step 5:2-[({8-[(2-methylbiphenyl-3-yl)amino]quinolin-3-yl}methyl)amino]ethanol

A mixture of 8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carbaldehyde(19 mg, 0.056 mmol) and ethanolamine (Aldrich, cat #398136: 10 μL, 0.167mmol) in methylene chloride (0.4 mL) and N,N-diisopropylethylamine (58.1μL, 0.333 mmol) was stirred at room temperature for 1 h then sodiumtriacetoxyborohydride (0.0353 g, 0.167 mmol) was carefully added. Thereaction mixture was stirred at room temperature for 24 h. The mixturewas concentrated, dissolved in methanol then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₅H₂₆N₃O (M+H)⁺: m/z=384.2; found 384.2. ¹HNMR (400 MHz, DMSO) δ 9.06 (s, 2H), 8.94 (d, J=2.0 Hz, 1H), 8.43 (d,J=2.0 Hz, 1H), 8.33 (s, 1H), 7.54-7.22 (m, 8H), 7.06 (d, J=7.6 Hz, 1H),7.00 (d, J=7.6 Hz, 1H), 5.18 (brs, 1H), 4.43 (t, J=5.2 Hz, 2H), 3.70 (t,J=5.2 Hz, 2H), 3.08 (brs, 2H), 2.14 (s, 3H).

Example 22-[({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)amino]ethanol

Step 1: 3-bromo-N-(2-methylbiphenyl-3-yl)-1,7-naphthyridin-8-amine

To a microwave vial was added 2-methylbiphenyl-3-amine (Example 1, Step1: 0.1 g, 0.546 mmol), 3-bromo-8-chloro-1,7-naphthyridine (PharmaBlock,cat #PBLJ2743: 140 mg, 0.55 mmol), tert-butyl alcohol (2.5 mL) and 4.0 Mhydrogen chloride in dioxane (0.136 mL, 0.546 mmol). The resultingmixture was irradiated in the microwave to 100° C. for 1 h. Theresulting mixture was concentrated, and the desired product was useddirectly in the next step. LC-MS calculated for C₂₁H₁₇N₃Br (M+H)⁺:m/z=390.1; found 390.1.

Step 2: N-(2-methylbiphenyl-3-yl)-3-vinyl-1,7-naphthyridin-8-amine

A mixture of 3-bromo-N-(2-methylbiphenyl-3-yl)-1,7-naphthyridin-8-amine(213 mg, 0.546 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(Aldrich, cat #633348: 0.185 mL, 1.09 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II)(Aldrich, cat #701998: 4 mg, 0.005 mmol) in tert-butyl alcohol (3.93 mL)and water (4 mL) was sparged with nitrogen then sealed. It was stirredat 110° C. for 2 h. The reaction mixture was cooled then extracted withethyl acetate (3×10 mL). The combined organic layers were washed withbrine, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude product was used directly in the next step withoutpurification. LC-MS calculated for C₂₃H₂₀N₃(M+H)⁺: m/z=338.2; found338.1.

Step 3:8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde

To a solution ofN-(2-methylbiphenyl-3-yl)-3-vinyl-1,7-naphthyridin-8-amine (184 mg, 0.55mmol) in 1,4-dioxane (11 mL) and water (11 mL) was added a 4 wt %solution of osmium tetraoxide in water (0.52 mL, 0.082 mmol). Themixture was stirred for 5 min then sodium periodate (467 mg, 2.18 mmol)was added and stirred for 1 h. The mixture was diluted with ethylacetate (10 mL), and the phases were separated. The aqueous layer wasextracted with ethyl acetate (10 mL) and the combined organic layerswere washed with water, then brine and were dried over sodium sulfate.The extract was filtered then concentrated in vacuo. The desiredaldehyde was purified by silica gel chromatography (0→40%EtOAc/hexanes). LC-MS calculated for C₂₂H₁₈N₃O (M+H)⁺: m/z=340.1; found340.1.

Step 4:2-[({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)amino]ethanol

This compound was prepared using a similar procedure as described forExample 1, Step 5, with8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde (Step3) replacing 8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carbaldehyde.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₂₅N₄O (M+H)⁺: m/z=385.2; found 385.2. ¹H NMR(400 MHz, DMSO) δ 9.24 (s, 2H), 9.10 (s, 1H), 8.50 (s, 1H), 7.88 (d,J=2.8 Hz, 2H), 7.52-7.35 (m, 6H), 7.28-7.18 (m, 2H), 5.02 (brs, 1H),4.49 (s, 2H), 3.71 (t, J=5.2 Hz, 2H), 3.11 (s, 2H), 2.18 (s, 3H).

Example 31-({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)piperidine-2-carboxylicacid

Step 1: methyl1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidine-2-carboxylate

A mixture of8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde(Example 2, Step 3: 65 mg, 0.19 mmol) and methyl pipecolinatehydrochloride (Aldrich, cat #391204: 100 mg, 0.574 mmol) in methylenechloride (2 mL) and N,N-diisopropylethylamine (200 μL, 1.15 mmol) wasstirred at room temperature for 1 h. Sodium triacetoxyborohydride(0.0353 g, 0.167 mmol) was carefully added and the mixture was stirredat room temperature for 24 h. The reaction mixture was quenched withsaturated sodium bicarbonate solution, and the organic layer wasseparated. The aqueous layer was further extracted with methylenechloride (2×10 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. The desired product wasobtained as an oil and was used in the next step without furtherpurification. LC-MS calculated for C₂₉H₃₁N₄O₂ (M+H)⁺: m/z=467.2; found467.2.

Step 2:1-({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)piperidine-2-carboxylicacid

To a mixture of methyl1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidine-2-carboxylate(88 mg, 0.19 mmol), tetrahydrofuran (0.66 mL), methanol (0.66 mL), andwater (0.33 mL) was added lithium hydroxide (275 mg, 11.5 mmol). Theresulting mixture was heated at 65° C. overnight. The mixture was cooledto room temperature, then adjusted to pH=1-2 with 1N HCl and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₈H₂₉N₄O₂ (M+H)⁺: m/z=453.2; found453.2. ¹H NMR (400 MHz, MeOD) δ 9.21 (d, J=1.8 Hz, 1H), 8.55 (d, J=1.8Hz, 1H), 7.61 (d, J=7.0 Hz, 1H), 7.57-7.36 (m, 8H), 7.33 (d, J=7.0 Hz,1H), 4.80 (m, 1H), 4.39 (d, J=13.4 Hz, 1H), 3.90 (d, J=10.4 Hz, 1H),3.48 (m, 1H), 3.16-3.00 (m, 1H), 2.34 (d, J=13.4 Hz, 1H), 2.22 (s, 3H),1.96-1.55 (m, 6H).

Example 41-({4-[(2-methylbiphenyl-3-yl)amino]pyrido[3,2-d]pyrimidin-7-yl}methyl)piperidine-2-carboxylicacid

Step 1: 7-bromo-N-(2-methylbiphenyl-3-yl)pyrido[3,2-d]pyrimidin-4-amine

To a vial was added 2-methylbiphenyl-3-amine (Example 1, Step 1: 0.4 g,2.18 mmol), 7-bromo-4-chloropyrido[3,2-d]pyrimidine (Ark Pharm, cat#AK-27560: 540 mg, 2.2 mmol), and isopropyl alcohol (10. mL) The mixturewas heated to 110° C. for 4 h. The mixture was cooled to roomtemperature, concentrated, and the crude product was used directly inthe next step without further purification. LC-MS calculated forC₂₀H₁₆BrN₄ (M+1)⁺: m/z=391.1; found 391.1.

Step 2: N-(2-methylbiphenyl-3-yl)-7-vinylpyrido[3,2-d]pyrimidin-4-amine

This compound was prepared using a similar procedure as described forExample 2, Step 2, with7-bromo-N-(2-methylbiphenyl-3-yl)pyrido[3,2-d]pyrimidin-4-amine (Step 1)replacing 3-bromo-N-(2-methylbiphenyl-3-yl)-1,7-naphthyridin-8-amine.The crude product was used directly in the next step without furtherpurification. LC-MS calculated for C₂₂H₁₉N₄ (M+1)⁺: m/z=339.2; found339.2.

Step 3:4-[(2-methylbiphenyl-3-yl)amino]pyrido[3,2-d]pyrimidine-7-carbaldehyde

This compound was prepared using a similar procedure as described forExample 2, Step 3, withN-(2-methylbiphenyl-3-yl)-7-vinylpyrido[3,2-d]pyrimidin-4-aminereplacing N-(2-methylbiphenyl-3-yl)-3-vinyl-1,7-naphthyridin-8-amine.The reaction mixture was stirred at room temperature for 18 h, and thenwas diluted with ethyl acetate (10 mL). The organic layer was separatedand the aqueous layer was further extracted with ethyl acetate (2×10mL). The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated in vacuo. The crude productwas used directly in the next step without further purification. LC-MScalculated for C₂₁H₁₇N₄O (M+1)⁺: m/z=341.1; found 341.1.

Step 4: methyl1-((4-(2-methylbiphenyl-3-ylamino)pyrido[3,2-d]pyrimidin-7-yl)methyl)piperidine-2-carboxylate

This compound was prepared using a similar procedure as described forExample 3, Step 1 with4-[(2-methylbiphenyl-3-yl)amino]pyrido[3,2-d]pyrimidine-7-carbaldehyde(Step 3) replacing8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde. Thecrude product was used directly in the next step without furtherpurification. LC-MS calculated for C₂₈H₃₀N₅ O₂ (M+1)⁺: m/z=468.2; found468.2.

Step 5:1-({4-[(2-methylbiphenyl-3-yl)amino]pyrido[3,2-d]pyrimidin-7-yl}methyl)piperidine-2-carboxylicacid

This compound was prepared using a similar procedure as described forExample 3, Step 2, with methyl1-((4-(2-methylbiphenyl-3-ylamino)pyrido[3,2-d]pyrimidin-7-yl)methyl)piperidine-2-carboxylate(Step 4) replacing methyl1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidine-2-carboxylate.The crude product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₈N₅O₂ (M+H)⁺: m/z=454.2; found 454.3.

Example 51-({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-4-yl}methyl)piperidine-2-carboxylicacid

Step 1: 4-chloro-N-(2-methylbiphenyl-3-yl)-1,7-naphthyridin-8-amine

To a vial was added 2-methylbiphenyl-3-amine (Example 1, Step 1: 0.2 g,1.09 mmol), 4,8-dichloro-1,7-naphthyridine (Synthonix, cat #D7291: 180mg, 0.91 mmol), and isopropyl alcohol (4 mL). The mixture was heated to100° C. for 4 h. The mixture was concentrated, and the crude product wasused directly in the next step. LC-MS calculated for C₂₁H₁₇ClN₃ (M+1)⁺:m/z=346.1; found 346.1.

Step 2: N-(2-methylbiphenyl-3-yl)-4-vinyl-1,7-naphthyridin-8-amine

This compound was prepared using a similar procedure as described forExample 2, Step 2, with4-chloro-N-(2-methylbiphenyl-3-yl)-1,7-naphthyridin-8-amine (Step 1)replacing 3-bromo-N-(2-methylbiphenyl-3-yl)-1,7-naphthyridin-8-amine.The crude product was used directly in the next step without furtherpurification. LC-MS calculated for C₂₃H₂₀N₃(M+1)⁺: m/z=338.2; found338.2.

Step 3:8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-4-carbaldehyde

This compound was prepared using a similar procedure as described forExample 2, Step 3, withN-(2-methylbiphenyl-3-yl)-4-vinyl-1,7-naphthyridin-8-amine (Step 2)replacing N-(2-methylbiphenyl-3-yl)-3-vinyl-1,7-naphthyridin-8-amine.The reaction mixture was stirred at room temperature for 18 h, and thenwas diluted with ethyl acetate (10 mL). The organic layer was separatedand the aqueous layer was further extracted with ethyl acetate (2×10mL). The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated in vacuo. The crude productwas purified by silica gel chromatography (0→50% EtOAc/hexanes). LC-MScalculated for C₂₂H₁₈N₃O (M+1)⁺: m/z=340.1; found 340.2.

Step 4: methyl1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-4-yl)methyl)piperidine-2-carboxylate

This compound was prepared using a similar procedure as described forExample 3, Step 1, with8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-4-carbaldehyde (Step3) replacing8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde. Thecrude product was used directly in the next step without furtherpurification. LC-MS calculated for C₂₉H₃₁N₄ O₂ (M+1)⁺: m/z=467.2; found467.2.

Step 5:1-({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-4-yl}methyl)piperidine-2-carboxylicacid

This compound was prepared using a similar procedure as described forExample 3, Step 2, with methyl1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-4-yl)methyl)piperidine-2-carboxylatereplacing methyl1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidine-2-carboxylate.The crude product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₉N₄O₂ (M+H)⁺: m/z=453.2; found 453.2. ¹H NMR(400 MHz, MeOD) δ 9.11 (d, J=4.4 Hz, 1H), 8.09 (d, J=4.4 Hz, 1H), 7.94(d, J=7.2 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.55-7.37 (m, 8H), 4.73 (d,J=13.8 Hz, 1H), 4.16 (d, J=13.8 Hz, 1H), 3.66-3.48 (m, 1H), 3.12 (m,1H), 2.71 (m, 1H), 2.24 (s, 3H), 2.20 (m, 1H) 1.94-1.52 (m, 6H).

Example 62-[({8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-4-yl}methyl)amino]ethanol

A mixture of8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-4-carbaldehyde(Example 5, Step 3: 0.022 g, 0.065 mmol) and ethanolamine in methylenechloride (1.00 mL) and N,N-diisopropylethylamine (67.7 μL, 0.389 mmol)was stirred at 50° C. for 1 h then sodium triacetoxyborohydride (0.0412g, 0.194 mmol) was carefully added. The reaction was stirred at 50° C.for 12 h. The mixture was cooled to room temperature, and thenconcentrated in vacuo. The residue was dissolved in methanol andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₄H₂₅N₄O (M+H)⁺:m/z=385.2; found 385.2. ¹H NMR (400 MHz, DMSO) δ 9.19 (s, 2H), 9.05 (d,J=4.8 Hz, 1H), 8.20-8.02 (m, 2H), 7.97 (d, J=3.6 Hz, 1H), 7.48 (dd,J=7.6, 7.2 Hz, 2H), 7.44-7.32 (m, 4H), 7.09 (m, 1H), 5.32 (brs, 1H),4.69 (m, 2H), 3.86-3.67 (m, 2H), 3.19 (m, 2H), 2.21 (s, 3H).

Example 72-[({8-[(2-methylbiphenyl-3-yl)amino]quinolin-4-yl}methyl)amino]ethanol

Step 1: 8-[(2-methylbiphenyl-3-yl)amino]quinoline-4-carbaldehyde

A mixture of 8-bromoquinoline-4-carbaldehyde (Oakwood Chemical, cat#042977: 100.0 mg, 0.4236 mmol), 2-methylbiphenyl-3-amine (Example 1,Step 1: 77.6 mg, 0.424 mmol),[(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (Aldrich, cat #761605: 58 mg, 0.064 mmol) and cesiumcarbonate (0.690 g, 2.12 mmol) in tert-butyl alcohol (10.0 mL) waspurged with nitrogen, and then stirred at 100° C. for 2 h. The mixturewas cooled to room temperature, diluted with ethyl acetate and water.The layers were separated and the organic layer was washed with brine,dried over sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography (0→50% EtOAc/hexanes).LC-MS calculated for C₂₃H₁₉N₂O (M+H)⁺: m/z=339.1; found 339.2.

Step 2:2-[({8-[(2-methylbiphenyl-3-yl)amino]quinolin-4-yl}methyl)amino]ethanol

This compound was prepared using a similar procedure as described forExample 1, Step 5, with8-[(2-methylbiphenyl-3-yl)amino]quinoline-4-carbaldehyde (Step 1)replacing 8-[(2-methylbiphenyl-3-yl)amino]quinoline-3-carbaldehyde. Thereaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₅H₂₆N₃O (M+H)⁺: m/z=384.2; found 384.2. ¹H NMR(400 MHz, DMSO) δ 9.13 (s, 2H), 8.94 (d, J=4.4 Hz, 1H), 8.43 (s, 1H),7.73 (d, J=4.4 Hz, 1H), 7.60-7.43 (m, 4H), 7.44-7.23 (m, 4H), 7.10-6.99(m, 2H), 5.32 (brs, 1H), 4.73 (m, 2H), 3.76 (t, J=5.2 Hz, 2H), 3.21 (s,2H), 2.15 (s, 3H).

Example 81-({8-[(2-methylbiphenyl-3-yl)amino]quinolin-4-yl}methyl)piperidine-2-carboxylicacid

Step 1: methyl1-((8-(2-methylbiphenyl-3-ylamino)quinolin-4-yl)methyl)piperidine-2-carboxylate

This compound was prepared using a similar procedure as described forExample 3, Step 1, with8-[(2-methylbiphenyl-3-yl)amino]quinoline-4-carbaldehyde (Example 7,Step 1) replacing8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde. Thecrude product was used directly in the next step without furtherpurification. LC-MS calculated for C₃₀H₃₂N₃O₂ (M+H)⁺: m/z=466.2; found466.2.

Step 2:1-({8-[(2-methylbiphenyl-3-yl)amino]quinolin-4-yl}methyl)piperidine-2-carboxylicacid

This compound was prepared using a similar procedure as described forExample 3, Step 2, with methyl1-((8-(2-methylbiphenyl-3-ylamino)quinolin-4-yl)methyl)piperidine-2-carboxylate(Step 1) replacing methyl1-((8-(2-methylbiphenyl-3-ylamino)-1,7-naphthyridin-3-yl)methyl)piperidine-2-carboxylate.The crude product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₀N₃O₂(M+H)⁺: m/z=452.2; found 452.3. ¹H NMR(400 MHz, MeOD) δ 8.93 (d, J=4.4 Hz, 1H), 7.77 (d, J=4.4 Hz, 1H), 7.71(d, J=8.4 Hz, 1H), 7.58 (dd, J=8.0, 7.8 Hz, 1H), 7.50-7.43 (m, 4H),7.40-7.30 (m, 4H), 7.11 (dd, J=15.2, 7.8 Hz, 2H), 5.14 (d, J=12.8 Hz,1H), 4.65 (m, 1H), 4.16 (d, J=11.2 Hz, 1H), 3.25-3.13 (m, 1H), 2.42 (d,J=11.2 Hz, 1H), 2.20 (s, 3H), 2.02-1.62 (m, 6H).

Example 92-[({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)amino]ethanol

Step 1: diethyl {[(2-chloropyridin-3-yl)amino]methylene}malonate

3-Amino-2-chloropyridine (Aldrich, cat #A46900: 5.71 g, 44.4 mmol) and(ethoxymethylene)propanedioic acid, diethyl ester (Alfa Aesar, cat#A13776: 9.013 mL, 44.6 mmol) were combined in a vial with a stir barand heated at 120° C. for 5 h. The resulting mixture was concentratedand washed with hexanes to provide the desired compound as a beigesolid. LC-MS calculated for C₁₃H₁₆ClN₂O₄(M+H)⁺: m/z=299.1; found 299.1.

Step 2: ethyl 8-chloro-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate

A three-neck flask was charged with diethyl{[(2-chloropyridin-3-yl)amino]methylene}malonate (6.39 g, 21.4 mmol), astir bar, and diphenyl ether (Aldrich, cat #240834: 102 mL). The mixturewas degassed for 10 min by bubbling nitrogen through the solution. AVigreux reflux condenser and temperature probe were then equipped andthe internal temperature of the reaction was heated to 240-250° C. for 1h. The reaction was then allowed to cool, and hexanes were added toprecipitate the product. The mixture was then filtered and theprecipitate was washed with hexanes. The solid was dried further usinghigh vacuum and used directly in the next step without furtherpurification. LC-MS calculated for C₁₁H₁₀ClN₂O₃(M+H)⁺: m/z=253.0; found253.1.

Step 3: ethyl8-(2-methylbiphenyl-3-ylamino)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate

To a vial was added 2-methylbiphenyl-3-amine (Example 1, Step 1: 0.457g, 2.49 mmol), ethyl 8-chloro-4-hydroxy-1,7-naphthyridine-3-carboxylate(630 mg, 2.5 mmol), cesium carbonate (2.44 g, 7.48 mmol),Brettphos-Pd-G3 precatalyst (Aldrich, cat #761605: 339 mg, 0.374 mmol),then tert-butyl alcohol (21 mL). The mixture was sparged with nitrogenfor 2 min, then sealed and heated at 100° C. for 2 h. After cooling tort, the mixture was filtered and the solid was washed with ethylacetate. The filtrate was concentrated in vacuo and purified by columnchromatography (0→20% MeOH/DCM). LC-MS calculated for C₂₄H₂₂N₃O₃ (M+H)⁺:m/z=400.2; found 400.2.

Step 4: ethyl4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carboxylate

A flask equipped with a Vigreux reflux condenser was charged with ethyl8-(2-methylbiphenyl-3-ylamino)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate(0.480 g, 1.20 mmol), a stir bar, and phosphoryl chloride (13 mL, 140mmol). The mixture was stirred at 110° C. for 1 h. The mixture wasconcentrated in vacuo and the remaining phosphoryl chloride was quenchedwith ice and slow addition of saturated sodium bicarbonate solution. DCMwas added to the mixture, and the layers were separated. The aqueouslayer was further extracted with DCM, and the combined organic extractswere dried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude residue was purified by column chromatography (0→40%EtOAc/hexanes). LC-MS calculated for C₂₄H₂₁ClN₃O₂ (M+H)⁺: m/z=418.1;found 418.2.

Step 5:{4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methanol

To a solution of ethyl4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carboxylate(0.550 g, 1.32 mmol) in tetrahydrofuran (13.8 mL, 1.70E2 mmol) was added1.0 M lithium tetrahydroaluminate in THF (1.32 mL, 1.32 mmol) at −78° C.dropwise. After addition, the reaction was stirred at this temperaturefor 30 min. The reaction was carefully quenched by adding aqueoussaturated ammonium chloride, then aqueous saturated Rochelle's salt wasadded and stirred for 1 h. The mixture was diluted with EtOAc, and thelayers were separated. The aqueous layer was further extracted withEtOAc, and the combined organic extracts were dried over sodium sulfate,filtered, and concentrated in vacuo. The crude solid was used directlyin the next step as a mixture of the title compound and thecorresponding aldehyde. LC-MS calculated for C₂₂H₁₉ClN₃O (M+H)⁺:m/z=376.1; found 376.2.

Step 6:4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde

To a solution of{4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methanol(464.0 mg, 1.234 mmol) in methylene chloride (11 mL) at 0° C. was addedDess-Martin periodinane (549.8 mg, 1.296 mmol). The mixture was stirredfor 1 h at 0° C. The reaction was quenched at this temperature withaqueous saturated sodium thiosulfate, and the layers were separated. Theaqueous layer was further extracted with methylene chloride. Thecombined organic layers were washed with sodium bicarbonate, water, andbrine and were dried over sodium sulfate, filtered, and concentrated invacuo. The crude residue was purified by chromatography using a pad ofsilica gel (0→1:1 EtOAc/hexanes). LC-MS calculated for C₂₂H₁₇ClN₃O(M+H)⁺: m/z=374.1; found 374.2.

Step 7:2-[({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)amino]ethanol

A mixture of4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde(0.008 g, 0.02 mmol) and ethanolamine (Aldrich, cat #398136: 3.87 μL,0.0642 mmol) in methylene chloride (0.2 mL) andN,N-diisopropylethylamine (22.4 μL, 0.128 mmol) was stirred at rt for 1h. sodium triacetoxyborohydride (0.0136 g, 0.0642 mmol) was carefullyadded in portions. The reaction was stirred at rt for 12 h. The iminewas observed using LC-MS (pH=10, water+NH₄OH), and to the mixture wasadded sodium borohydride (4.05 mg, 0.107 mmol) and a few drops ofmethanol. The reaction was stirred at rt for 2 h, then was diluted withmethanol and purified by prep HPLC (pH=2, water+TFA) to provide thedesired product as the TFA salt. LC-MS calculated for C₂₄H₂₄ClN₄O(M+H)⁺: m/z=419.2; found 419.1.

Example 102-[({4-methoxy-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)amino]ethanol

Step 1:4-methoxy-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde

4-Chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde(Example 9, Step 6: 20.0 mg, 0.0535 mmol), methanol (1.0 mL), andpotassium carbonate (8.87 mg, 0.0642 mmol) were combined in a vial andheated at 60° C. whilst stirring for 1 h. The mixture was diluted withethyl acetate, filtered, and concentrated in vacuo. The resulting yellowresidue was used directly in the next step. LC-MS calculated forC₂₃H₂₀N₃O₂ (M+H)⁺: m/z=370.1; found 370.2.

Step 2:2-[({4-methoxy-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)amino]ethanol

This compound was prepared using a similar procedure as described forExample 9, Step 7 with4-methoxy-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehydereplacing4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₅H₂₇N₄O₂ (M+H)⁺: m/z=415.2; found 415.2.

Example 111-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)piperidine-2-carboxylicacid

Step 1: methyl1-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)piperidine-2-carboxylate

A mixture of4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde(Example 9, Step 6: 0.020 g, 0.053 mmol) and methylpiperidine-2-carboxylate hydrochloride (Aldrich, cat #391204: 28.8 mg,0.160 mmol) in methylene chloride (0.4 mL) and N,N-diisopropylethylamine(55.9 μL, 0.321 mmol) was stirred at rt for 1 h. Sodiumtriacetoxyborohydride (0.0340 g, 0.160 mmol) was carefully added inportions. The reaction was stirred at rt for 2 h. The resulting iminewas observed by LC-MS (pH=10, water+NH₄OH) and to the reaction mixturewas added a few drops of methanol and sodium tetrahydroborate (10.1 mg,0.267 mmol). The mixture was stirred for 1 h, then quenched with anaqueous solution of saturated sodium bicarbonate. The organic layer wasseparated and the aqueous layer was further extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude residue was used directly in the nextstep. LC-MS calculated for C₂₉H₃₀ClN₄O₂(M+H)⁺: m/z=501.2; found 501.2.

Step 2:1-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)piperidine-2-carboxylicacid

To a vial charged with methyl1-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)piperidine-2-carboxylate(26.8 mg, 0.0535 mmol) was added lithium hydroxide (12.81 mg, 0.5350mmol), methanol (0.5 mL), THF (0.5 mL), and water (0.5 mL). The mixturewas heated to 60° C. whilst stirring for 2 h. After cooling to rt, themixture was acidified using aqueous 1 N HCl, diluted with methanol, andpurified by prep HPLC (pH=2, water+TFA) to provide the desired compoundas the TFA salt. LC-MS calculated for C₂₈H₂₈ClN₄O₂(M+H)⁺: m/z=487.2;found 487.2.

Example 122-{[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-naphthyridin-4-yl)methyl]amino}ethanol

Step 1: 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylaniline

A mixture of 3-bromo-2-methylaniline (Aldrich, cat #530018: 1.00 mL,8.12 mmol), 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (Combi-Blocks,cat #BB-8311: 1.9 g, 10. mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (Aldrich, cat #379670: 0.05 g, 0.06 mmol) andpotassium carbonate (2.72 g, 19.7 mmol) in 1,4-dioxane (41.2 mL) andwater (20 mL) was degassed and recharged with nitrogen three times. Themixture was then heated and stirred at 110° C. for 1.5 h. The reactionmixture was quenched with saturated aqueous NaHCO₃, and extracted withethyl acetate (3×10 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The resulting residue was purified by column chromatography(0→30% EtOAc/hexanes). LC-MS calculated for C₁₅H₁₆NO₂ (M+H)⁺: m/z=242.1;found 242.2.

Step 2:4-chloro-N-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-1,7-naphthyridin-8-amine

To a vial was added 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylaniline(0.263 g, 1.09 mmol), 4,8-dichloro-1,7-naphthyridine (Synthonix, cat#D7291: 180 mg, 0.91 mmol), and acetonitrile (10.0 mL). The reaction washeated to 100° C. for 4 h. After cooling to rt, cesium carbonate (0.296g, 0.910 mmol) was added and the mixture was then refluxed for 4 h.After cooling to rt, the mixture was diluted with ethyl acetate,filtered, and concentrated in vacuo. LC-MS calculated forC₂₃H₁₉ClN₃O₂(M+H)⁺: m/z=404.1; found 404.1.

Step 3:N-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-4-vinyl-1,7-naphthyridin-8-amine

A mixture ofN-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-4-vinyl-1,7-naphthyridin-8-amine(0.370 g, 0.936 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(Aldrich, cat #633348: 1.59 mL, 9.36 mmol), sodium carbonate (0.198 g,1.87 mmol) and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II)(Aldrich, cat #701998: 7.1 mg, 0.0094 mmol) in tert-butyl alcohol (6.73mL) and water (6 mL) was degassed and sealed. The mixture was stirred at110° C. for 2 h. The reaction mixture was cooled then extracted withethyl acetate (3×20 mL). The combined organic layers were washed withbrine, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was used directly in the next step withoutfurther purification. LC-MS calculated for C₂₅H₂₂N₃O₂ (M+1)⁺: m/z=396.2;found 396.2.

Step 4:8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-naphthyridine-4-carbaldehyde

A flask was charged withN-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-4-vinyl-1,7-naphthyridin-8-amine(370. mg, 0.936 mmol), 1,4-dioxane (20. mL), a stir bar and water (20.mL). To this suspension was added a 4% w/w mixture of osmium tetraoxidein water (0.89 mL, 0.14 mmol). The reaction was stirred for 5 min thensodium periodate (2001 mg, 9.356 mmol) was added. After stirring at rtfor 1 h, the reaction was quenched with a saturated aqueous solution ofsodium thiosulfate. The mixture was then extracted with ethyl acetate(2×10 mL), and the combined organic layers were separated, washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The cruderesidue was purified by column chromatography (0→60% EtOAc/hexanes).LC-MS calculated for C₂₄H₂₀N₃O₃ (M+H)⁺: m/z=398.1; found 398.2.

Step 5:2-{[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-naphthyridin-4-yl)methyl]amino}ethanol

This compound was prepared using a similar procedure as described forExample 9, Step 7 with8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-naphthyridine-4-carbaldehydereplacing4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₇N₄O₃ (M+H)⁺: m/z=443.2; found 443.3.

Example 131-[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-naphthyridin-4-yl)methyl]piperidine-2-carboxylicacid

Step 1: methyl1-((8-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenylamino)-1,7-naphthyridin-4-yl)methyl)piperidine-2-carboxylate

This compound was prepared using a similar procedure as described forExample 11, Step 1 with8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-naphthyridine-4-carbaldehyde(Example 12, Step 4) replacing4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridine-3-carbaldehyde.The crude compound was used directly in the next step without furtherpurification. LC-MS calculated for C₃₁H₃₃N₄O₄ (M+H)⁺: m/z=525.2; found525.2.

Step 2:1-[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-naphthyridin-4-yl)methyl]piperidine-2-carboxylicacid

This compound was prepared using a similar procedure as described forExample 11, Step 2 with methyl1-((8-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenylamino)-1,7-naphthyridin-4-yl)methyl)piperidine-2-carboxylatereplacing methyl1-({4-chloro-8-[(2-methylbiphenyl-3-yl)amino]-1,7-naphthyridin-3-yl}methyl)piperidine-2-carboxylate.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₀H₃₁N₄O₄ (M+H)⁺: m/z=511.2; found 511.3.

Example 142-[({5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazin-2-yl}methyl)amino]ethanol

Step 1: 5-chloropyrido[3,4-b]pyrazin-2(1H)-one

A suspension of 2-chloropyridine-3,4-diamine (Aldrich, cat #736376: 0.5g, 3 mmol) and ethyl glyoxylate (1:1 w/v in toluene, Alfa Aesar, cat#L19207: 0.73 mL, 3.6 mmol) in ethanol (5.0 mL) was heated at 90° C.overnight. The mixture was then cooled at −20° C. for 2 d. Theprecipitate was filtered, washed with cold ethanol, collected, and useddirectly in the next step without further purification. LC-MS calculatedfor C₇H₅ClN₃O (M+H)⁺: m/z=182.0; found 182.1.

Step 2: 5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazin-2-ol

A degassed mixture of 2-methylbiphenyl-3-amine (Example 1, Step 1: 0.020g, 0.11 mmol), 5-chloropyrido[3,4-b]pyrazin-2(1H)-one (0.020 g, 0.11mmol), cesium carbonate (0.107 g, 0.327 mmol) and Brettphos Pd G3precatalyst (Aldrich, cat #761605: 7.9 mg, 0.0087 mmol) in tert-butylalcohol (0.3 mL) was heated at 100 deg ° C. for 2 h. 1.0 M hydrogenchloride in water was added until the pH was ˜ 5. After stirringovernight, the precipitate was filtered, and the solid was dried andused directly in the next step. LC-MS calculated for C₂₀H₁₇N₄O (M+H)⁺:m/z=329.1; found 329.2.

Step 3: 2-chloro-N-(2-methylbiphenyl-3-yl)pyrido[3,4-b]pyrazin-5-amine

A mixture of 5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazin-2-ol(0.25 g, 0.76 mmol) in phosphoryl chloride (2.5 mL, 27 mmol) was heatedat 120° C. in a sealed vial for 1.5 h. The reaction was cooled andconcentrated in vacuo. The resulting black residue was dissolved in1,2-dichloroethane and cooled to 0° C. An aqueous saturated solution ofsodium bicarbonate was added and stirred for 1 h at rt. The precipitatewas filtered and the filtrate was washed with brine, dried over sodiumsulfate, filtered, and concentrated. The black solid was then trituratedwith tert-butyl methyl ether (3 mL), and the resulting precipitate wasfiltered and washed to give the desired product as a dark brown solid.The filtrate was then purified using column chromatography (0→30%EtOAc/hexanes) to provide the desired product as a dark brown solid.LC-MS calculated for C₂₀H₁₆ClN₄ (M+H)⁺: m/z=347.1; found 347.1.

Step 4: N-(2-methylbiphenyl-3-yl)-2-vinylpyrido[3,4-b]pyrazin-5-amine

A degassed mixture of2-chloro-N-(2-methylbiphenyl-3-yl)pyrido[3,4-b]pyrazin-5-amine (0.25 g,0.72 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (Aldrich, cat #741825: 0.063 g, 0.080 mmol), potassium phosphate(0.47 g, 2.2 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(Aldrich, cat #663348: 0.18 mL, 1.1 mmol) in 1,4-dioxane (2.5 mL) andwater (0.8 mL) was refluxed at 120° C. for 2.5 h. The mixture was cooledto rt, and ethyl acetate and water were added. The resulting mixture wasstirred for 1 h, and the precipitate was filtered and washed. Theorganic filtrate was washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo. The crude residue was purified usingflash chromatography (0→30% EtOAc/hexanes) to provide the desiredcompound as an orange solid. LC-MS calculated for C₂₂H₁₉N₄ (M+H)⁺:m/z=339.2; found 339.2.

Step 5:5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazine-2-carbaldehyde

This compound was prepared using a similar procedure as described forExample 12, Step 4 withN-(2-methylbiphenyl-3-yl)-2-vinylpyrido[3,4-b]pyrazin-5-amine replacingN-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-4-vinyl-1,7-naphthyridin-8-amine.The crude compound was used directly in the next step without furtherpurification. LC-MS calculated for C₂₁H₁₇N₄O₂ (M+H₂O)⁺: m/z=359.1; found359.2.

Step 6:2-[({5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazin-2-yl}methyl)amino]ethanol

To a solution of5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazine-2-carbaldehyde(3.0 mg, 0.0088 mmol) in methylene chloride (1 mL) was addedethanolamine (Aldrich, cat #398136: 10.0 μL, 0.166 mmol) and acetic acid(10.0 □L, 0.176 mmol). The mixture was stirred at rt for 20 min, thensodium triacetoxyborohydride (31 mg, 0.15 mmol) was added and stirred atrt for 1 h. Water and a saturated solution of NaHCO₃ were added. Thelayers were separated and the organic layer was concentrated anddissolved in THF/MeOH. The desired product was purified by prep HPLC(pH=10, water+NH₄OH, then a second purification using pH=2, water+TFA)to provide the compound as the TFA salt. LC-MS calculated for C₂₃H₂₄N₅₀(M+H)⁺: m/z=386.2; found 386.2.

Example 15(2S)-1-({5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazin-2-yl}methyl)piperidine-2-carboxylicacid

A suspension of5-[(2-methylbiphenyl-3-yl)amino]pyrido[3,4-b]pyrazine-2-carbaldehyde(Example 14, Step 5: 0.022 g, 0.065 mmol), (2S)-piperidine-2-carboxylicacid (Alfa Aesar, cat #L15373: 15 mg, 0.12 mmol) and acetic acid (10.0μL, 0.176 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) wasstirred for 2 min. Sodium cyanoborohydride (9.0 mg, 0.14 mmol) was addedand stirred at rt for 4.5 h. The mixture was diluted with methanol andpurified by prep HPLC (pH=10, water+NH₄OH, then a second purificationusing pH=2, water+TFA) to provide the desired compound as the TFA salt.LC-MS calculated for C₂₇H₂₈N₅O₂ (M+H)⁺: m/z=454.2; found 454.3.

Example 162-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)amino]benzonitrile

Step 1: 2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile

A mixture of 2-amino-6-bromobenzonitrile (Combi-blocks, cat #SS-7081:3.0 g, 15 mmol), 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid(Combi-Blocks, cat #BB-8311: 3.6 g, 20. mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (Aldrich, cat #379670: 0.1 g, 0.1 mmol) andpotassium carbonate (5.11 g, 36.9 mmol) in 1,4-dioxane (77 mL) and water(30 mL) was degassed and recharged with nitrogen three times. Themixture was then heated and stirred at 120° C. for 1.5 h. The reactionmixture was quenched with saturated aqueous NaHCO₃, and extracted withethyl acetate (3×10 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The beige solid was used directly in the next step. LC-MScalculated for C₁₅H₁₃N₂O₂(M+H)⁺: m/z=253.1; found 253.2.

Step 2: 8-chloro-3-vinyl-1,7-naphthyridine

A mixture of 3-bromo-8-chloro-1,7-naphthyridine (PharmaBlock, cat#PBLJ2743: 0.200 g, 0.821 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich, cat #663348:153 μL, 0.904 mmol), sodium carbonate (0.174 g, 1.64 mmol) and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II)(Aldrich, cat #701998: 6.2 mg, 0.0082 mmol) in tert-butyl alcohol (5.91mL) and water (6 mL) was degassed and sealed. It was stirred at 110° C.for 2 h. The reaction mixture was cooled then extracted with ethylacetate (3×20 mL). The combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude residue was used directly in the next step without furtherpurification. LC-MS calculated for C₁₀H₈ClN₂ (M+H)⁺: m/z=191.0; found191.0.

Step 3: 8-chloro-1,7-naphthyridine-3-carbaldehyde

This compound was prepared using a similar procedure as described forExample 12, Step 4 with 8-chloro-3-vinyl-1,7-naphthyridine replacingN-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]-4-vinyl-1,7-naphthyridin-8-amine.The crude compound was used directly in the next step without furtherpurification. LC-MS calculated for C₉H₆ClN₂O (M+H)⁺: m/z=193.0; found192.9.

Step 4: 2-{[(8-chloro-1,7-naphthyridin-3-yl)methyl]amino}ethanol

A mixture of 8-chloro-1,7-naphthyridine-3-carbaldehyde (0.160 g, 0.831mmol) and ethanolamine (Aldrich, cat #398136: 251 μL, 4.15 mmol) inmethylene chloride (6 mL) and N,N-diisopropylethylamine (868 μL, 4.98mmol) was stirred at rt for 1 h. Sodium triacetoxyborohydride (0.528 g,2.49 mmol) was carefully added in portions. The reaction was stirred atrt for 2 h. To the mixture was then carefully added sodiumtetrahydroborate (157 mg, 4.15 mmol) and methanol (1 mL) and thereaction mixture was stirred overnight under nitrogen. The reaction wasquenched with a saturated aqueous solution of sodium bicarbonate. Themixture was then extracted with a 3:1 mixture of chloroform/isopropylalcohol. The combined organic layers were washed with brine, dried oversodium sulfate, then concentrated in vacuo. The crude residue waspurified by column chromatography (0→50% methanol/DCM) and was obtainedas an off white solid. LC-MS calculated for C₁₁H₁₃ClN₃O (M+H)⁺:m/z=238.1; found 238.1.

Step 5:2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)amino]benzonitrile

To a vial was added2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile (0.0106 g,0.0421 mmol), 2-{[(8-chloro-1,7-naphthyridin-3-yl)methyl]amino}ethanol(10.00 mg, 0.04207 mmol), cesium carbonate (0.0274 g, 0.0841 mmol),1,4-dioxane (1 mL),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Aldrich, cat#526460: 4.9 mg, 0.0084 mmol), andtris(dibenzylideneacetone)dipalladium(0) (Aldrich, cat #328774: 4.4 mg,0.0042 mmol). The mixture was sparged with nitrogen for 20 s, then thevial was sealed and heated to 110° C. for 2 h whilst stirring. Themixture was cooled to rt, diluted with methanol, and purified by prepHPLC (pH=2, water+TFA) to provide the compound as the TFA salt. LC-MScalculated for C₂₆H₂₄N₅O₃ (M+H)⁺: m/z=454.2; found 454.2.

Example 172-{[(8-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]amino}-1,7-naphthyridin-3-yl)methyl]amino}ethanol

To a vial was added 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylaniline(Example 12, Step 1: 0.0102 g, 0.0421 mmol),2-{[(8-chloro-1,7-naphthyridin-3-yl)methyl]amino}ethanol (Example 16,Step 4: 10.00 mg, 0.04207 mmol), cesium carbonate (0.0274 g, 0.0841mmol), 1,4-dioxane (1.00 mL),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Aldrich, cat#526460: 4.9 mg, 0.0084 mmol), andtris(dibenzylideneacetone)dipalladium(0) (Aldrich, cat #328774: 4.4 mg,0.0042 mmol). The mixture was sparged with nitrogen for 20 s and thevial was sealed and heated to 110° C. whilst stirring for 2 h. Thereaction was cooled, diluted with methanol, then purified by prep HPLC(pH=2, water+TFA) to provide the compound as a TFA salt. LC-MScalculated for C₂₆H₂₇N₄O₃ (M+H)⁺: m/z=443.2; found 443.2.

Example 182-[({8-[(3-cyclohex-1-en-1-yl-2-methylphenyl)amino]-1,7-naphthyridin-3-yl}methyl)amino]ethanol

Step 1:2-[({8-[(3-bromo-2-methylphenyl)amino]-1,7-naphthyridin-3-yl}methyl)amino]ethanol

To a microwave vial was added 3-bromo-2-methylaniline (Aldrich, cat#530018: 29.5 μL, 0.240 mmol),2-{[(8-chloro-1,7-naphthyridin-3-yl)methyl]amino}ethanol (Example 16,Step 4: 57.00 mg, 0.2398 mmol), tert-butyl alcohol (1.1 mL) and 4.0 Mhydrogen chloride in dioxane (59.0 μL, 0.236 mmol). The reaction wasirradiated to 100° C. for 1 h in the microwave. After cooling to rt, themixture was concentrated in vacuo, and the desired compound was purifiedby column chromatography (0→50% methanol/DCM). LC-MS calculated forC₁₈H₂₀BrN₄O (M+H)⁺: m/z=387.1; found 387.1.

Step 2:2-[({8-[(3-cyclohex-1-en-1-yl-2-methylphenyl)amino]-1,7-naphthyridin-3-yl}methyl)amino]ethanol

A mixture of2-[({8-[(3-bromo-2-methylphenyl)amino]-1,7-naphthyridin-3-yl}methyl)amino]ethanol(0.0150 g, 0.0387 mmol),2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Aldrich,cat #650277: 0.0242 g, 0.116 mmol), sodium carbonate (0.00821 g, 0.0775mmol) and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II)(Aldrich, cat #701998: 0.29 mg, 0.00039 mmol) in tert-butyl alcohol(0.279 mL) and water (0.3 mL) was degassed and sealed. The mixture wasstirred at 90° C. for 2 h. The reaction was cooled, diluted withmethanol, then purified by prep HPLC (pH=10, water+NH₄OH). LC-MScalculated for C₂₄H₂₉N₄O (M+H)⁺: m/z=389.2; found 389.3.

Example 193-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)amino]biphenyl-2-carbonitrile

Step 1: 3-aminobiphenyl-2-carbonitrile

This compound was prepared using a similar procedure as described forExample 16, Step 1 with phenylboronic acid (Aldrich, cat #P20009)replacing 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid. The crudecompound was purified using column chromatography (0→50% EtOAc/hexanes).LC-MS calculated for C₁₃H₁₁N₂ (M+H)⁺: m/z=195.1; found 195.2.

Step 2:3-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)amino]biphenyl-2-carbonitrile

This compound was prepared using a similar procedure as described forExample 16, Step 5 with 3-aminobiphenyl-2-carbonitrile replacing2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile. The reactionmixture was purified using prep HPLC (pH=2, water+TFA) to provide thecompound as the TFA salt. LC-MS calculated for C₂₄H₂₂N₅₀ (M+H)⁺:m/z=396.2; found 396.3.

Example 202-cyclohex-1-en-1-yl-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)amino]benzonitrile

Step 1: 2-amino-6-cyclohex-1-en-1-ylbenzonitrile

This compound was prepared using a similar procedure as described forExample 16, Step 1 with2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Aldrich,cat #650277) replacing 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid. Thecrude compound was purified using column chromatography (0→50%EtOAc/hexanes). LC-MS calculated for C₁₃H₁₅N₂ (M+H)⁺: m/z=199.1; found199.1.

Step 2:2-cyclohex-1-en-1-yl-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)amino]benzonitrile

This compound was prepared using a similar procedure as described forExample 16, Step 5 with 2-amino-6-cyclohex-1-en-1-ylbenzonitrilereplacing 2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile. Thereaction mixture was purified using prep HPLC (pH=2, water+TFA) toprovide the compound as the TFA salt. LC-MS calculated for C₂₄H₂₆N₅₀(M+H)⁺: m/z=400.2; found 400.3.

Example 212-cyclohexyl-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)amino]benzonitrile

Step 1: 2-amino-6-cyclohexylbenzonitrile

A mixture of 2-amino-6-cyclohex-1-en-1-ylbenzonitrile (Example 20, Step1: 100 mg, 0.5 mmol) and 10% palladium on carbon (53 mg, 0.050 mmol) inmethanol (5 mL) was stirred under an atmosphere of hydrogen at roomtemperature for 1.5 h. The reaction mixture was filtered through celiteand the filtrate was concentrated in vacuo. The desired compound wasused directly in the next step without further purification. LC-MScalculated for C₁₃H₁₇N₂(M+H)⁺: m/z=201.1; found 201.2.

Step 2:2-cyclohexyl-6-[(3-{[(2-hydroxyethyl)amino]methyl}-1,7-naphthyridin-8-yl)amino]benzonitrile

This compound was prepared using a similar procedure as described forExample 16, Step 5 with 2-amino-6-cyclohexylbenzonitrile replacing2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile. The reactionmixture was purified using prep HPLC (pH=2, water+TFA) to provide thecompound as the TFA salt. LC-MS calculated for C₂₄H₂₈N₅O (M+H)⁺:m/z=402.2; found 402.3.

Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)Binding Assay

The assays were conducted in a standard black 384-well polystyrene platewith a final volume of 20 μL. Inhibitors were first serially diluted inDMSO and then added to the plate wells before the addition of otherreaction components. The final concentration of DMSO in the assay was1%. The assays were carried out at 25° C. in the PBS buffer (pH 7.4)with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein(19-238) with a His-tag at the C-terminus was purchased fromAcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) withFc tag at the C-terminus was also purchased from AcroBiosystems(PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay bufferand 10 μL was added to the plate well. Plates were centrifuged andproteins were preincubated with inhibitors for 40 minutes. Theincubation was followed by the addition of 10 μL of HTRF detectionbuffer supplemented with Europium cryptate-labeled anti-human IgG(PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated toSureLight®-Allophycocyanin (APC, PerkinElmer-AD0059H). Aftercentrifugation, the plate was incubated at 25° C. for 60 min. beforereading on a PHERAstar FS plate reader (665 nm/620 nm ratio). Finalconcentrations in the assay were −3 nM PD1, 10 nM PD-L1, 1 nM europiumanti-human IgG and 20 nM anti-His-Allophycocyanin. IC₅₀ determinationwas performed by fitting the curve of percent control activity versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Compounds of the present disclosure, as exemplified in the Examples,showed IC₅₀ values in the following ranges: +=IC₅₀≤10 nM; ++=10nM<IC₅₀≤100 nM; +++=100 nM<IC₅₀≤1000 nM.

Data obtained for the Example compounds using the PD-1/PD-L1 homogenoustime-resolved fluorescence (HTRF) binding assay described in Example Ais provided in Table 1.

TABLE 1 PD-1/PD-L1 HTRF Example IC₅₀ (nM) 1 ++ 2 + 3 ++ 4 ++ 5 + 6 ++ 7++ 8 ++ 9 ++ 10 + 11 ++ 12 + 13 ++ 14 + 15 ++ 16 + 17 + 18 + 19 + 20 +21 ++

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X¹ is CR¹; X² isCR², X³ is CR³, X⁴ is N; X⁵ is CR⁵; X⁶ is N; R¹ is H; R², R³, and R⁹ areeach independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a),C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a),NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a),S(O)NR^(a)R^(a), S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R², R³, andR⁹ are each optionally substituted with 1, 2, 3, or 4 R^(b)substituents; R⁵ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; R⁷ is CH₃ or CN;each R^(g) is H; or two adjacent R^(g) substituents together with thecarbon atoms to which they are attached, form a fused phenyl ring, afused 5- to 7-membered heterocycloalkyl ring, a fused 5- or 6-memberedheteroaryl ring or a fused C₃₋₁₀ cycloalkyl ring, wherein the fused 5-to 7-membered heterocycloalkyl ring and fused 5- or 6-memberedheteroaryl ring each have 1-4 heteroatoms as ring members selected fromN, O and S and wherein the fused phenyl ring, fused 5- to 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₁₀ cycloalkyl ring are each optionally substituted with 1 or 2independently selected R^(q) substituents; each R^(a) is independentlyselected from H, CN, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆-10 aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; each R^(d) isindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5- or 6-memberedheteroaryl, CN, NH₂, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e)e, NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, phenyl,5- or 6-membered heteroaryl and 4-10 membered heterocycloalkyl of R^(d)are each further optionally substituted with 1-3 independently selectedR^(q) substituents; each R^(b) substituent is independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) orS(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each further optionallysubstituted with 1-3 independently selected R^(d) substituents; eachR^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(o) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituents;each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents; each R^(n) is independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, R^(o), NHOR^(o),OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o),OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o),NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o),NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o); eachR^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆-10 aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1-3 independently selected R^(p)substituents; or any two R^(a) substituents together with the nitrogenatom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3R^(h) substituents; each R^(h) is independently selected from C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i),NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i),OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6membered heteroaryl)-C₁₋₄ alkyl-, and (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each further optionallysubstituted by 1, 2, or 3 R^(j) substituents; each R^(j) isindependently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-memberedheteroaryl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k),C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k),NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k),C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k),S(O)NR^(k)R^(k), S(O)₂R^(k), NRS(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), andS(O)₂NR^(k)R^(k); or two R^(h) groups attached to the same carbon atomof the 4- to 10-membered heterocycloalkyl taken together with the carbonatom to which they are attached form a C₃₋₆ cycloalkyl or 4- to6-membered heterocycloalkyl having 1-2 heteroatoms as ring membersselected from O, N or S; or any two R^(c) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(e) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any two R^(b)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; and each R^(e), R^(i), R^(k), R^(o) or R^(p) isindependently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5 or 6-membered heteroaryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(e), R^(i),R^(k), R^(o) or R^(p) are each optionally substituted with 1, 2 or 3R^(q) substituents; each R^(q) is independently selected from OH, CN,—COOH, NH₂, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, phenyl, 4- to6-membered heterocycloalkyl, 5- or 6-membered heteroaryl, C₃₋₆cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄ haloalkoxy, wherein the C₁₋₄ alkyl,phenyl, 4- to 6-membered heterocycloalkyl and 5- or 6-memberedheteroaryl of R^(q) are each optionally substituted with 1 or 2substituents independently selected from halo, OH, CN, —COOH, NH₂, C₁₋₄alkyl, C₁₋₄ alkoxy, C₃₋₁₀ cycloalkyl and 4-, 5-, or 6-memberedheterocycloalkyl; each R¹² is independently C₁₋₆ alkyl; the subscript nis an integer of 1, 2, 3, 4 or 5; and the subscript m is an integer of1, 2 or
 3. 2. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R² is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR a, SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a),OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a) C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R² are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents.
 3. The compound ofclaim 1, having Formula (III):

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, having Formula (IV):

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, having Formula (V):

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, having Formula (VI):

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R³ is halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a) C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³ are each optionally substituted with1, 2, 3, or 4 R^(b) substituents.
 8. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R³ is selected from H,CN, C₁₋₆ alkyl and halo.
 9. The compound of claim 7, or apharmaceutically acceptable salt thereof, wherein R² is selected from H,CN, C₁₋₆ alkyl and halo.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is —CH₂—R^(b). 11.The compound of claim 10, or a pharmaceutically acceptable salt thereof,wherein R^(b) is —NR^(c)R^(c).
 12. The compound of claim 1, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R³is —CH₂—R^(b).
 13. The compound of claim 12, or a pharmaceuticallyacceptable salt thereof, wherein R^(b) is —NR^(c)R^(c).
 14. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R² is2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl,(S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl or(3-cyanobenzyl)oxy.
 15. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R³ is 2-hydroxyethylaminomethyl,2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl,(R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy.
 16. Thecompound of claim 1, wherein the compound is1-({4-[(2-methylbiphenyl-3-yl)amino]pyrido[3,2-d]pyrimidin-7-yl}methyl)piperidine-2-carboxylicacid, or a pharmaceutically acceptable salt thereof.
 17. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 18. The compound of claim 1, havingFormula (III):

or a pharmaceutically acceptable salt thereof; wherein R³ is selectedfrom H, CN, C₁₋₆ alkyl and halo; R² is —CH₂—R^(b); and R^(b) is—NR^(c)R^(c).
 19. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is —CH₂—R^(b); R^(b) is—NR^(c)R^(c); R³ is H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, CN, or OR^(a);and R⁵ is H or C₁₋₆ haloalkyl.
 20. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is —CH₂—R^(b);R^(b) is —NR^(c)R^(c); R³ is H; and R⁵ is C₁₋₆ haloalkyl.
 21. A methodof inhibiting growth of tumor cells in vitro, said method comprisingcontacting the tumor cells with a compound of claim 1, or apharmaceutically acceptable salt thereof.